N-hydroxylsulfonamide derivatives as new physiologically useful nitroxyl donors

ABSTRACT

The invention relates to N-hydroxysulfonamide derivatives that donate nitroxyl (HNO) under physiological conditions and are useful in treating and/or preventing the onset and/or development of diseases or conditions that are responsive to nitroxyl therapy, including heart failure and ischemia/reperfusion injury. Novel N-hydroxysulfonamide derivatives release NHO at a controlled rate under physiological conditions, and the rate of HNO release is modulated by varying the nature and location of functional groups on the N-hydroxysulfonamide derivatives.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationSer. No. 60/783,556, filed Mar. 17, 2006 and entitled“N-Hyroxylsulfonamide Derivatives as New Physiologically Useful NitroxylDoners,” which is incorporated herein by reference in its entirety.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made in part with government support under Grant No.CHE-0518406 from the National Science Foundation. The government mayhave certain rights in this invention.

BACKGROUND OF THE INVENTION Summary of Heart Failure

Congestive heart failure (CHF) is a generally progressive, lifethreatening condition in which myocardial contractility is depressedsuch that the heart is unable to adequately pump the blood returning toit, also referred to as decompensation. Symptoms include breathlessness,fatigue, weakness, leg swelling, and exercise intolerance. On physicalexamination, patients with heart failure often have elevated heart andrespiratory rates (an indication of fluid in the lungs), edema, jugularvenous distension, and enlarged hearts. The most common cause of CHF isatherosclerosis, which causes blockages in the coronary arteries thatprovide blood flow to the heart muscle. Ultimately, such blockages maycause myocardial infarction with subsequent decline in heart functionand resultant heart failure. Other causes of CHF include valvular heartdisease, hypertension, viral infections of the heart, alcoholconsumption, and diabetes. Some cases of CHF occur without clearetiology and are called idiopathic. The effects of CHF on a subjectexperiencing the condition can be fatal.

There are several types of CHF. Two types of CHF are identifiedaccording to which phase of the cardiac pumping cycle is more affected.Systolic heart failure occurs when the heart's ability to contractdecreases. The heart cannot pump with enough force to push a sufficientamount of blood into the circulation leading to a reduced leftventricular ejection fraction. Lung congestion is a typical symptom ofsystolic heart failure. Diastolic heart failure refers to the heart'sinability to relax between contractions and allow enough blood to enterthe ventricles. Higher filling pressures are required to maintaincardiac output, but contractility as measured by left ventricularejection fraction is typically normal. Swelling (edema) in the abdomenand legs is a typical symptom of diastolic heart failure. Often, anindividual experiencing heart failure will have some degree of bothsystolic heart failure and diastolic heart failure.

CHF is also classified according to its severity. The New York HeartAssociation classifies CHF into four classes: Class I involves noobvious symptoms, with no limitations on physical activity; Class IIinvolves some symptoms during or after normal activity, with mildphysical activity limitations; Class III involves symptoms with lessthan ordinary activity, with moderate to significant physical activitylimitations; and Class IV involves significant symptoms at rest, withsevere to total physical activity limitations. Typically, an individualprogresses through the classes as they live with the condition.

Although CHF is generally thought of as a chronic, progressivecondition, it can also develop suddenly. This type of CHF is calledacute CHF, and it is a medical emergency. Acute CHF can be caused byacute myocardial injury that affects either myocardial performance, suchas myocardial infarction, or valvular/chamber integrity, such as mitralregurgitation or ventricular septal rupture, which leads to an acuterise in left ventricular and diastolic pressure resulting in pulmonaryedema and dyspnea.

Common treatment agents for CHF include vasodilators (drugs that dilateblood vessels), positive inotropes (drugs that increase the heart'sability to contract), and diuretics (drugs to reduce fluid).Additionally, beta-antagonists (drugs that antagonize beta-adrenergicreceptors) have become standard agents for treating mild to moderateheart failure. Lowes et al, Clin. Cardiol., 23:11111-6 (2000).

Positive inotropic agents include beta-adrenergic agonists, such asdopamine, dobutamine, dopexamine, and isoproterenol. However, use of abeta-agonist has potential complications, such as arrhythmogenesis andincreased oxygen demand by the heart. Additionally, the initialshort-lived improvement of myocardial contractility afforded by thesedrugs is followed by an accelerated mortality rate resulting largelyfrom a greater frequency of sudden death. Katz, HEART FAILURE:PATHOPHYSIOLOGY, MOLECULAR BIOLOGY AND CLINICAL MANAGEMENT, Lippincott,Williams & Wilkins (1999).

Beta-antagonists antagonize beta-adrenergic receptor function. Whileinitially contra-indicated in heart failure, they have been found toprovide a marked reduction in mortality and morbidity in clinicaltrials. Bouzamondo et al., Fundam. Clin. Pharmacol., 15: 95-109 (2001).Accordingly, they have become an established therapy for heart failure.However, even subjects that improve under beta-antagonist therapy maysubsequently decompensate and require acute treatment with a positiveinotropic agent. Unfortunately, as their name suggests, beta-antagonistsblock the mechanism of action of the positive inotropic beta-agoniststhat are used in emergency care centers. Bristow et al., J. Card. Fail.,7: 8-12 (2001).

Vasodilators, such as nitroglycerin, have been used for a long period oftime to treat heart failure. However, the cause of nitroglycerin'stherapeutic effect was not known until late in the last century when itwas discovered that the nitric oxide molecule (NO) was responsible fornitroglycerin's beneficial effects. In some subjects experiencing heartfailure, a nitric oxide donor is administered in combination with apositive inotropic agent to both cause vasodilation and to increasemyocardial contractility. However, this combined administration canimpair the effectiveness of positive inotropic treatment agents. Forexample, Hart et al, Am. J. Physiol. Heart Circ. Pyhsiol., 281:146-54(2001) reported that administration of the nitric oxide donor sodiumnitroprusside, in combination with the positive inotropic,beta-adrenergic agonist dobutamine, impaired the positive inotropiceffect of dobutamine. Hare et al., Circulation, 92:2198-203 (1995) alsodisclosed the inhibitory effect of nitric oxide on the effectiveness ofdobutamine.

As described in U.S. Pat. No. 6,936,639, compounds that donate nitroxyl(HNO) under physiological conditions have both positive inotropic andlusitropic effects and offer significant advantages over existingtreatments for failing hearts. Due to their concomitant positiveinotropic/lusotropic action and unloading effects, nitroxyl donors werereported as helpful in treating cardiovascular diseases characterized byhigh resistive load and poor contractile performance. In particular,nitroxyl-donating compounds were reported as useful in the treatment ofheart failure, including heart failure in individuals receivingbeta-antagonist therapy.

Summary of Ischemia

Ischemia is a condition characterized by an interruption or inadequatesupply of blood to tissue, which causes oxygen deprivation in theaffected tissue. Myocardial ischemia is a condition caused by a blockageor constriction of one or more of the coronary arteries, such as canoccur with atherosclerotic plaque occlusion or rupture. The blockade orconstriction causes oxygen deprivation of the non-perfused tissue, whichcan cause tissue damage. Further, upon reperfusion with subsequentreoxygenation of the tissue, when the blood is able to flow again or theoxygen demand of the tissue subsides, additional injury can be caused byoxidative stress.

Ischemia/reperfusion injury refers to tissue damage caused by oxygendeprivation followed by reoxygenation. The effects ofischemia/reperfusion injury in a subject experiencing the condition canbe fatal, particularly when the injury occurs in a critical organ suchas the heart or brain.

Accordingly, compounds and compositions effective in preventing orprotecting against ischemia/reperfusion injury would be usefulpharmaceuticals. Compounds such as nitroglycerin have been used for along period of time to help control vascular tone and protect againstmyocardial ischemia/reperfusion injury. It was discovered that thenitric oxide molecule was responsible for nitroglycerin's beneficialeffects. This discovery prompted interest in medical uses for nitricoxide and investigations into related species such as nitroxyl. Asreported in U.S. patent application Ser. No. 10/463,084 (U.S.Publication No. 2004/0038947) administration of a compound that donatesnitroxyl under physiological conditions, prior to ischemia, canattenuate ischemia/reperfusion injury to tissues, for example,myocardial tissues. This beneficial effect was reported as a surprisingresult given that nitroxyl was previously reported to increaseischemia/reperfusion injury (See, Ma et al., “Opposite Effects of NitricOxide and Nitroxyl on Postischemic Myocardial Injury,” Proc. Nat'l Acad.Sci., 96(25): 14617-14622 (1999), reporting that administration ofAngeli's salt (a nitroxyl donor under physiological conditions) toanesthetized rabbits during ischemia and 5 minutes prior to reperfusionincreased myocardial ischemia/reperfusion injury and Takahira et al.,“Dexamethasone Attenuates Neutrophil Infiltration in the Rat Kidney inIschemia/Reperfusion Injury: The Possible Role of Nitroxyl,” FreeRadical Biology & Medicine, 31(6):809-815 (2001) reporting thatadministration of Angeli's salt during ischemia and 5 minutes beforereperfusion of rat renal tissue contributed to neutrophil infiltrationinto the tissue, which is believed to mediate ischemia/reperfusioninjury). In particular, pre-ischemic administration of Angeli's salt andisopropylamine/NO has been reported to prevent or reduceischemia/reperfusion injury.

Summary of Nitroxyl Donors

To date, the vast majority of studies of the biological effect of HNOhave used the donor sodium dioxotrinitrate (“Angeli's salt” or “AS”).However, the chemical stability of AS has made it unsuitable to developas a therapeutic agent. N-hydroxybenzenesulfonamide (“Piloty's acid” or“PA”) has previously been shown to be a nitroxyl donor at high ph (>9)(Bonner, F. T.; Ko, Y. Inorg. Chem. 1992, 31, 2514-2519). However, underphysiological conditions, PA is a nitric oxide donor via an oxidativepathway (Zamora, R.; Grzesiok, A.; Weber, H.; Feelisch, M. Biochem. J.1995, 312, 333-339). Thus, the physiological effects of AS and PA arenot the same because AS is a nitroxyl donor under physiologicalconditions whereas PA is a nitric oxide donor under physiologicalconditions.

Although U.S. Pat. No. 6,936,639 and U.S. Publication No. 2004/0038947describe PA as a compound that donates nitroxyl and note that othersulfohydroxamic acids and their derivatives are therefore also useful asnitroxyl donors, PA does not in fact donate significant amounts ofnitroxyl under physiological conditions (See Zamora, supra).

Several substituted N-hydroxylbenzenesulfonamides have been reported asinhibitors of carbonic anhydrase, with no mention of HNO production(see, (a) Mincione, F.; Menabuoni, L.; Briganti., F; Mincione, G.;Scozzafava, A.; Supuran, C. T. J. Enzyme Inhibition 1998, 13, 267-284and (b) Scozzafava, A.; Supuran, C. T., J. Med. Chem. 2000, 43,3677-3687).

Significant Medical Need

Despite efforts towards the development of new therapies for thetreatment of diseases and conditions such as heart failure andischemia/reperfusion injury, there remains a significant interest in andneed for additional or alternative compounds that treat or prevent theonset or severity of these and related diseases or conditions. Inparticular, there remains a significant medical need for alternative oradditional therapies for the treatment of diseases or conditions thatare responsive to nitroxyl therapy. New compounds that donate nitroxylunder physiological conditions and methods of using compounds thatdonate nitroxyl under physiological conditions may thus find use astherapies for treating, preventing and/or delaying the onset and/ordevelopment of diseases or conditions responsive to nitroxyl therapy,including heart disease and ischemia/reperfusion injury. Preferably, thetherapeutic agents can improve the quality of life and/or prolong thesurvival time for patients with the disease or condition.

BRIEF SUMMARY OF THE INVENTION

Methods, compounds and compositions for treating and/or preventing theonset or development of diseases or conditions that are responsive tonitroxyl therapy are described. Aromatic and non-aromaticN-hydroxylsulfonamide derivatives that donate nitroxyl underphysiological conditions are described. By modifying PA with appropriatesubstituents, such as electron-withdrawing groups or groups thatsterically hinder the sulfonyl moiety, the HNO producing capacity ofthese derivatives is substantially enhanced under physiologicalconditions. Significantly, when compared to AS, PA has the capacity forbroad substituent modification, enabling optimization of physicochemicaland pharmacological properties. Such optimization is reported herein.

In one embodiment, the present invention provides a method ofadministering to a subject in need thereof, a therapeutically effectiveamount of a derivative of PA wherein the derivative donates nitroxylunder physiological conditions. In one embodiment, the inventionembraces a method of treating or preventing the onset and/or developmentof a disease or condition that is responsive to nitroxyl therapy, themethod comprising administering to an individual in need thereof anN-hydroxylsulfonamide that donates an effective amount of nitroxyl underphysiological conditions. Also embraced are methods of treating heartfailure or ischemia/reperfusion injury by administering to an individualin need thereof an N-hydroxysulfonamide that donates an effective amountof nitroxyl under physiological conditions.

Kits comprising the compounds are also described, which may optionallycontain a second therapeutic agent such as a positive inotropiccompound, which may be, e.g., a beta-adrenergic receptor agonist.

Novel compounds that find use in the invention described herein includecompounds of the formula (I), (II), (III) or (IV):

where R¹ is H; R² is H, aralkyl or heterocyclyl; m and n areindependently an integer from 0 to 2; x and b are independently aninteger from 0 to 4; y is an integer from 0 to 3; T is an alkyl orsubstituted alkyl; Z is an electron withdrawing group; R³, R⁴, R⁵, R⁶and R⁷ are independently selected from the group consisting of H, halo,alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano,alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl,alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl,dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl andarylsulfinyl, provided that: (1) at least one of R³, R⁴, R⁵, R⁶ and R⁷is other than H; (2) at least one of R³, R⁴, R⁵, R⁶ and R⁷ is other thanhalo; (3) when R³, R⁴, R⁶ and R⁷ are H, R⁵ is other than halo, nitro,cyano, alkyl or alkoxy; (4) when one of R³ or R⁷ is halo and the R³ orR⁷ that is not halo is H and one of R⁴ or R⁶ is halo and the R⁴ or R⁶that is not halo is H, R⁵ is other than halo; (5) when R³, R⁷ and R⁵ areH and one of R⁴ and R⁶ is H, the R⁴ or R⁶ that is not H is other thanN-hydroxysulfonamidyl, perhaloalkyl or nitro; (6) when R⁴, R⁵ and R⁶ areH and one of R³ and R⁷ is H, the R³ or R⁷ that is not H is other thannitro or alkyl; (7) when R³ and R⁷ are H, R⁵ is nitro and one of R⁴ andR⁶ is H, the R⁴ or R⁶ that is not H is other than halo; (8) when R⁴ andR⁶ are nitro and R³ and R⁷ are H, R⁵ is other than dialkylamino; (9)when R⁴ and R⁶ are H and R³ and R⁷ are alkyl, R⁵ is other than alkyl;and (10) when R³ and R⁷ are H and R⁴ and R⁶ are nitro, R⁵ is other thandialkylamino; each R⁸ and R⁹ is independently selected from the groupconsisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl,nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy,alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substitutedheterocycloalkyl, dialkylamino, NH₂, OH, C(O)OH, C(O)Oalkyl,NHC(O)alkylC(O)OH, C(O)NH₂, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH,NHC(O)NH₂, OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH₂, cycloalkoxy,cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; A is a cycloalkyl,heterocycloalkyl, aromatic or heteroaromatic ring containing ringmoieties Q¹, Q², Q³ and Q⁴, which are taken together with V and W toform ring A; B is a cycloalkyl, heterocycloalkyl, aromatic orheteroaromatic ring containing ring moieties Q⁵, Q⁶, Q⁷ and Q⁸, whichare taken together with the V and W to form ring B; V and W areindependently C, CH, N or Ne; Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷ and Q⁸ areindependently selected from the group consisting of C, CH₂, CH, N, NR¹⁰,O and S, provided that either (1) when rings A and B form naphthalene, xis an integer from 1 to 3 or y is an integer from 2 to 4 or R⁸ is otherthan Cl or (2) at least one of Q¹, Q², Q³, Q⁴, Q⁵, Q⁶, Q⁷ and Q⁸ is N,NR¹⁰, O or S; C is a heteroaromatic ring containing ring moieties Q⁹,Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ that are independently selected from thegroup consisting of C, CH₂, CH, N, NR¹⁰, O and S, provided that at leastone of Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ is N, NR¹⁰, O or S; and R¹⁰ is H,alkyl, acyl or sulfonyl. Pharmaceutically acceptable salts of any of theforegoing are also described. In one variation, the compound is of theformula (I), (II), (III) or (IV) where R¹ is H; R² is H; m and n areindependently an integer from 0 to 2; x and b are independently aninteger from 0 to 4; y is an integer from 0 to 3; T is an alkyl orsubstituted alkyl; Z is an electron withdrawing group; R³, R⁴, R⁵, R⁶and R⁷ are independently selected from the group consisting of H, halo,alkylsulfonyl, substituted alkylsulfonyl, N-hydroxylsulfonamidyl,substituted N-hydroxylsulfonamidyl, perhaloalkyl, substitutedperhaloalkyl (where one or more halo may be substituted with asubstituent), nitro, aryl, substituted aryl, cyano, alkoxy, substitutedalkoxy, perhaloalkoxy, substituted perhaloalkoxy, alkyl, substitutedalkyl, aryloxy, substituted aryloxy, alkylsulfanyl, substitutedalkylsulfanyl, alkylsulfinyl, substituted alkylsulfinyl,heterocycloalkyl, substituted heterocycloalkyl, dialkylamino,substituted dialkylamino, cycloalkoxy, substituted cycloalkoxy,cycloalkylsulfanyl, substituted cycloalkylsulfanyl, arylsulfanyl,substituted arylsulfanyl, arylsulfinyl and substituted arylsulfinyl,provided that: (1) at least one of R³, R⁴, R⁵, R⁶, R⁷ is other than H;(2) at least one of R³, R⁴, R⁵, R⁶ and R⁷ is other than halo; (3) whenR³, R⁴, R⁶ and R⁷ are H, R⁵ is other than halo, nitro, cyano, alkyl oralkoxy; (4) when one of R³ or R⁷ is halo and the R³ or R⁷ that is nothalo is H and one of R⁴ or R⁶ is halo and the R⁴ or R⁶ that is not halois H, R⁵ is other than halo; (5) when R³, R⁷ and R⁵ are H and one of R⁴and R⁶ is H, the R⁴ or R⁶ that is not H is other thanN-hydroxysulfonamidyl, perhaloalkyl or nitro; (6) when R⁴, R⁵ and R⁶ areH and one of R³ and R⁷ is H, the R³ or R⁷ that is not H is other thannitro or alkyl; (7) when R³ and R⁷ are H, R⁵ is nitro and one of R⁴ andR⁶ is H, the R⁴ or R⁶ that is not H is other than halo; (8) when R⁴ andR⁶ are nitro and R³ and R⁷ are H, R⁵ is other than dialkylamino; (9)when R⁴ and R⁶ are H and R³ and R⁷ are alkyl, R⁵ is other than alkyl;and (10) when R³ and R⁷ are H and R⁴ and R⁶ are nitro, R⁵ is other thandialkylamino; each R⁸ and R⁹ is independently selected from the groupconsisting of halo, alkylsulfonyl, substituted alkylsulfonyl,N-hydroxylsulfonamidyl, substituted N-hydroxylsulfonamidyl,perhaloalkyl, substituted perhaloalkyl, nitro, aryl, substituted aryl,cyano, alkoxy, substituted alkoxy, perhaloalkoxy, substitutedperhaloalkoxy, alkyl, substituted alkyl, aryloxy, substituted aryloxy,alkylsulfanyl, substituted alkylsulfanyl, alkylsulfinyl, substitutedalkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl,dialkylamino, substituted dialkylamino, NH₂, OH, C(O)OH, C(O)Oalkyl,NHC(O)alkylC(O)OH, C(O)NH₂, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH,NHC(O)NH₂, OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH₂, cycloalkoxy,substituted cycloalkoxy, cycloalkylsulfanyl, substitutedcycloalkylsulfanyl, arylsulfanyl, substituted arylsulfanyl, arylsulfinyland substituted arylsulfinyl (where any listing of alkyl or alkenyl inthe moieties above intends unsubstituted or substituted alkyl oralkenyl); A is a cycloalkyl, heterocycloalkyl, aromatic orheteroaromatic ring containing ring moieties Q¹, Q², Q³ and Q⁴, whichare taken together with V and W to form ring A; B is a cycloalkyl,heterocycloalkyl, aromatic or heteroaromatic ring containing ringmoieties Q⁵, Q⁶, Q⁷ and Q⁸, which are taken together with the V and W toform ring B; V and W are independently C, CH, N or NR¹⁰; Q¹, Q², Q³, Q⁴,Q⁵, Q⁶, Q⁷ and Q⁸ are independently selected from the group consistingof C, CH₂, CH, N, NR¹⁰, O and S, provided that either (1) when rings Aand B form naphthalene, x is an integer from 1 to 3 or y is an integerfrom 2 to 4 or R⁸ is other than Cl or (2) at least one of Q¹, Q², Q³,Q⁴, Q⁵, Q⁶, Q⁷ and Q⁸ is N, NR¹⁰, O or S; C is a heteroaromatic ringcontaining ring moieties Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ that areindependently selected from the group consisting of C, CH₂, CH, N, NR¹⁰,O and S, provided that at least one of Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ isN, NR¹⁰, O or S; and R¹⁰ is H, alkyl, acyl or sulfonyl. Pharmaceuticallyacceptable salts of any of the foregoing are also described.

Methods are also described, including a method of treating, preventingor delaying the onset or development of a disease or condition that isresponsive to nitroxyl therapy, comprising administering to anindividual in need thereof an N-hydroxysulfonamide that donates nitroxylunder physiological conditions or a pharmaceutically acceptable saltthereof. In one variation, the method comprises administering to theindividual a compound of the formula:

where R¹ is H; R² is H; m and n are independently an integer from 0 to2; x and b are independently an integer from 0 to 4; y is an integerfrom 0 to 3; T is an alkyl or substituted alkyl; Z is an electronwithdrawing group; R³, R⁴, R⁵, R⁶ and R⁷ are independently selected fromthe group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl,perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl,substituted heterocycloalkyl, dialkylamino, cycloalkoxy,cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided that: (1) atleast one of R³, R⁴, R⁵, R⁶ and R⁷ is other than H; each R⁸ and R⁹ isindependently a substituent; A is a cycloalkyl, heterocycloalkyl,aromatic or heteroaromatic ring containing ring moieties Q¹, Q², Q³ andQ⁴, which are taken together with V and W to form ring A; B is acycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ring containingring moieties Q⁵, Q⁶, Q⁷ and Q⁸, which are taken together with V and Wto form ring B; V and W are independently C, CH, N or NR¹⁰; Q¹, Q², Q³,Q⁴, Q⁵, Q⁶, Q⁷ and Q⁸ are independently selected from the groupconsisting of C, CH₂, CH, N, NR¹⁰, O and S; C is a heteroaromatic ringcontaining ring moieties Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ that areindependently selected from the group consisting of C, CH₂, CH, N, NR¹⁰,O and S; and R¹⁰ is H, alkyl, acyl or sulfonyl.

Pharmaceutical compositions comprising a compound of the invention aredisclosed, such as pharmaceutical compositions that are amenable tointravenous injection. Kits comprising a compound of the invention andinstructions for use are also described.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the nitrous oxide headspace analysis of compounds testedas nitroxyl donors as compared to the nitrous oxide headspace analysisof the nitroxyl donor Angeli's Salt (AS). Nitrous oxide (N₂O) is theproduct of nitroxyl (HNO) dimerization and is thus indicative of whethera compound is a nitroxyl donor under the test conditions.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless clearly indicated otherwise, the following terms as used hereinhave the meanings indicated below.

Use of the terms “a”, “an” and the like refers to one or more.

“Aralkyl” refers to a residue in which an aryl moiety is attached to theparent structure via an alkyl residue. Examples include benzyl(—CH₂-Ph), phenethyl (—CH₂CH₂Ph), phenylvinyl (—CH═CH-Ph), phenylallyland the like.

“Acyl” refers to and includes the groups —C(O)H, —C(O)alkyl,—C(O)substituted alkyl, —C(O)alkenyl, —C(O)substituted alkenyl,—C(O)alkynyl, —C(O)substituted alkynyl, —C(O)cycloalkyl,—C(O)substituted cycloalkyl, —C(O)aryl, —C(O)substituted aryl,—C(O)heteroaryl, —C(O)substituted heteroaryl, —C(O)heterocyclic, and—C(O)substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein or otherwise known in the art.

“Heterocyclyl” or “Heterocycloalkyl” refers to a cycloalkyl residue inwhich one to four of the carbons is replaced by a heteroatom such asoxygen, nitrogen or sulfur. Examples of heterocycles whose radicals areheterocyclyl groups include tetrahydropyran, morpholine, pyrrolidine,piperidine, thiazolidine, oxazole, oxazoline, isoxazole, dioxane,tetrahydrofuran and the like. A specific example of a heterocyclylresidue is tetrahydropyran-2-yl.

“Substituted heterocylco” or “substituted heterocylcoalkyl” refers to anheterocyclyl group having from 1 to 5 substituents. For instance, aheterocyclyl group substituted with 1 to 5 groups such as halo, nitro,cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino, hydroxyl,carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl, —OS(O)₂-alkyl,and the like is a substituted alkyl. A particular example of asubstituted heterocylcoalkyl is N-methylpiperazino.

“Alkyl” intends linear hydrocarbon structures having 1 to 20 carbonatoms, preferably 1 to 12 carbon atoms and more preferably 1 to 8 carbonatoms. Alkyl groups of fewer carbon atoms are embraced, such asso-called “lower alkyl” groups having 1 to 4 carbon atoms. “Alkyl” alsointends branched or cyclic hydrocarbon structures having 3 to 20 carbonatoms, preferably 3 to 12 carbon atoms and more preferably 3 to 8 carbonatoms. For any use of the term “alkyl,” unless clearly indicatedotherwise, it is intended to embrace all variations of alkyl groupsdisclosed herein, as measured by the number of carbon atoms, the same asif each and every alkyl group was explicitly and individually listed foreach usage of the term. For instance, when a group such as R³ may be an“alkyl,” intended is a C₁-C₂₀ alkyl or a C₁-C₁₂ alkyl or a C₁-C₈ alkylor a lower alkyl or a C₂-C₂₀ alkyl or a C₃-C₁₂ alkyl or a C₃-C₈ alkyl.The same is true for other groups listed herein, which may includegroups under other definitions, where a certain number of atoms islisted in the definition. When the alkyl group is cyclic, it may also bereferred to as a cycloalkyl group and have e.g., 1 to 20 annular carbonatoms, preferably 1 to 12 annular carbon atoms and more preferably 1 to8 annular carbon atoms. When an alkyl residue having a specific numberof carbons is named, all geometric isomers having that number of carbonsare intended to be encompassed; thus, for example, “butyl” is meant toinclude n-butyl, sec-butyl, iso-butyl and t-butyl; “propyl” includesn-propyl and iso-propyl. Examples of alkyl groups include methyl, ethyl,n-propyl, propyl, t-butyl, n-heptyl, octyl, cyclopentyl, cyclopropyl,cyclobutyl, norbornyl, and the like. One or more degrees of unsaturationmay occur in an alkyl group. Thus, an alkyl group also embraces alkenyland alkynyl residues. “Alkenyl” is understood to refer to a group of 2or more carbon atoms, such as 2 to 10 carbon atoms and more preferably 2to 6 carbon atoms and having at least 1 and preferably from 1-2 sites ofalkenyl unsaturation. Examples of an alkenyl group include —C═CH₂,—CH₂CH═CHCH₃ and —CH₂CH═CH—CH═CH₂. “Alkynyl” refers to alkynyl grouppreferably having from 2 to 10 carbon atoms and more preferably 3 to 6carbon atoms and having at least 1 and preferably from 1-2 sites ofalkynyl unsaturation, such as the moiety —CCH. Alkyl is also used hereinto denote an alkyl residue as part of a larger functional group and whenso used, is taken together with other atoms to form another functionalgroup. For instance, reference to —C(O)Oalkyl intends an esterfunctional group, where the alkyl portion of the moiety may be any alkylgroup, and provide by way of example only, the functional group—C(O)OCH₃, —C(O)(O)CH═CH₂ and the like. Another example of an alkylgroup as part of a larger structure includes the residue—NHC(O)alkylC(O)OH, which e.g., may be NHC(O)CH₂CH₂C(O)OH when alkyl is—CH₂CH₂—.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents. For instance, an alkyl group substituted with a group suchas halo, nitro, cyano, oxo, aryl, alkoxy, acyl, acylamino, amino,hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,—OS(O)₂-alkyl, and the like is a substituted alkyl. Likewise,“substituted alkenyl” and “substituted alkynyl” refer to alkenyl oralkynyl groups having 1 to 5 substituents.

As used herein the term “substituent” or “substituted” means that ahydrogen radical on a compound or group (such as, for example, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, aralkyl, substituted aralkyl,heteroaryl, substituted heteroaryl, heteroaralkyl, substitutedheteroaralkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl,substituted heterocycloalkyl, heterocyclyl and substituted heterocyclyl)is replaced′ with any desired group that does not substantiallyadversely affect the stability of the compound. In one embodiment,desired substituents are those which do not adversely affect theactivity of a compound. The term “substituted” refers to one or moresubstituents (which may be the same or different), each replacing ahydrogen atom. Examples of substituents include, but are not limited to,halogen (F, Cl, Br, or 1), hydroxyl, amino, alkylamino, arylamino,dialkylamino, diarylamino, cyano, nitro, mercapto, oxo (i.e., carbonyl),thio, imino, formyl, carbamido, carbamyl, carboxyl, thioureido,thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, alkyl, alkenyl,alkoxy, mercaptoalkoxy, aryl, heteroaryl, cyclyl, heterocyclyl, whereinalkyl, alkenyl, alkyloxy, aryl, heteroaryl, cyclyl, and heterocyclyl areoptionally substituted with alkyl, aryl, heteroaryl, halogen, hydroxyl,amino, mercapto, cyano, nitro, oxo (═O), thioxo (═S), or imino(═Nalkyl). In other embodiments, substituents on any group (such as, forexample, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, aralkyl,substituted aralkyl, heteroaryl, substituted heteroaryl, heteroaralkyl,substituted heteroaralkyl, cycloalkyl, substituted cycloalkyl,heterocycloalkyl, substituted heterocycloalkyl, heterocyclyl andsubstituted heterocyclyl) can be at any atom of that group (such as on acarbon atom of the primary carbon chain of a substituted alkyl group oron a substituent already present on a substituted alkyl group) or at anyatom of, wherein any group that can be substituted (such as, forexample, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl,heteroaralkyl, cycloalkyl, cyclyl, heterocycloalkyl, and heterocyclyl)can be optionally substituted with one or more substituents (which maybe the same or different), each replacing a hydrogen atom. Examples ofsuitable substituents include, but not limited to alkyl, alkenyl,alkynyl, cyclyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aralkyl,heteroaralkyl, aryl, heteroaryl, halogen, haloalkyl, cyano, nitro,alkoxy, aryloxy, hydroxyl, hydroxylalkyl, oxo (i.e., carbonyl),carboxyl, formyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl,alkylcarbonyloxy, aryloxycarbonyl, heteroaryloxy, heteroaryloxycarbonyl,thio, mercapto, mercaptoalkyl, arylsulfonyl, amino, aminoalkyl,dialkylamino, alkylcarbonylamino, alkylaminocarbonyl, oralkoxycarbonylamino; alkylamino, arylamino, diarylamino, alkylcarbonyl,or arylamino-substituted aryl; arylalkylamino, aralkylaminocarbonyl,amido, alkylaminosulfonyl, arylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, arylsulfonylamino, imino, carbamido, carbamyl,thioureido, thiocyanato, sulfoamido, sulfonylalkyl, sulfonylaryl, ormercaptoalkoxy. Additional suitable substituents on alkyl, alkenyl,alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cyclyl,heterocycloalkyl, and heterocyclyl include, without limitation halogen,CN, NO₂, OR¹¹, SR¹¹, S(O)₂OR¹¹, NR¹¹R¹², C₁-C₂perfluoroalkyl, C₁-C₂perfluoroalkoxy, 1,2-methylenedioxy, (═O), (═S), (═NR¹¹), C(O)OR¹¹,C(O)R¹¹R¹², OC(O)NR¹¹R¹², NR¹¹C(O)NR¹¹R¹², C(NR¹²)NR¹¹R¹²,NR¹¹C(NR¹²)NR¹¹R¹², S(O)₂NR¹¹R¹²R¹³, C(O)H, C(O)R¹³, NR¹¹C(O)R¹³,Si(R¹¹)₃, OSi(R¹¹)₃, Si(OH)₂R¹¹, B(OH)₂, P(O)(OR¹¹)₂, S(O)R¹³, orS(O)₂R¹³. Each R¹¹ is independently hydrogen, C₁-C₆ alkyl optionallysubstituted with cycloalkyl, aryl, heterocyclyl, or heteroaryl. Each R¹²is independently hydrogen, C₃-C₆ cycloalkyl, aryl, heterocyclyl,heteroaryl, C₁-C₄ alkyl or C₁-C₄ alkyl substituted with C₃-C₆cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R¹³ is independentlyC₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁-C₄ alkyl or C₁-C₄alkyl substituted with C₃-C₆ cycloalkyl, aryl, heterocyclyl orheteroaryl. Each C₃-C₆ cycloalkyl, aryl, heterocyclyl, heteroaryl andC₁-C₄ alkyl in each R¹¹, R¹² and R¹³ can optionally be substituted withhalogen, CN, C₁-C₄ alkyl, OH, C₁-C₄ alkoxy, COOH, C(O)OC₁-C₄ alkyl, NH₂,C₁-C₄ alkylamino, or C₁-C₄ dialkylamino. Substituents can also be“electron-withdrawing groups.”

“Electron withdrawing group” refers to groups that reduce electrondensity of the moiety to which they are attached (relative to thedensity of the moiety without the substituent). Such groups include, forexample, F, Cl, Br, I, —CN, —CF₃, —NO₂, —SH, —C(O)H, —C(O)alkyl,—C(O)Oalkyl, —C(O)OH, —C(O)Cl, —S(O)₂OH, —S(O)₂NHOH, —NH₃ and the like.

“Halo” refers to fluorine, chlorine, bromine or iodine.

“Alkylsulfonyl” refers to groups —SO₂alkyl and —SO₂substituted alkyl,which includes the residues —SO₂cycloalkyl, —SO₂substituted cycloalkyl,—SO₂alkenyl, —SO₂substituted alkenyl, —SO₂alkynyl, —SO₂substitutedalkynyl, where alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl areas defined herein.

“N-hydroxylsulfonamidyl” refers to —S(O)₂NROH, where R is H or alkyl.

“Perhaloalkyl” refers to an alkyl group where each H of the hydrocarbonis replaced with F. Examples of perhalo groups include —CF₃ and —CF₂CF₃.

“Aryl” intends a monocyclic, bicyclic or tricyclic aromatic ring. Anaryl group is preferably a 5- or 6-membered aromatic or heteroaromaticring containing 0-3 annular heteroatoms selected from O, N, or S; abicyclic 9- or 10-membered aromatic or heteroaromatic ring system(meaning the ring system has 9 or 10 annular atoms) containing 0-3annular heteroatoms selected from O, N, or S; or a tricyclic 13- or14-membered aromatic or heteroaromatic ring system (meaning the ringsystem has 13 or 14 annular atoms) containing 0-3 annular heteroatomsselected from O, N, or S. Examples of groups whose radicals are arylgroups include e.g., benzene, naphthalene, indane, tetralin, imidazole,pyridine, indole, thiophene, benzopyranone, thiazole, furan,benzimidazole, benzoxazole, benzthiazole, quinoline, isoquinoline,quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.

“Substituted aryl” refers to a group having from 1 to 3 substituents.For instance, an aryl group substituted with 1 to 3 groups such as halo,nitro, cyano, oxo, aryl, alkoxy, alkyl, acyl, acylamino, amino,hydroxyl, carboxyl, carboxylalkyl, thiol, thioalkyl, heterocyclyl,—OS(O)₂-alkyl, and the like is a substituted aryl.

“Alkoxy” refers to an alkyl group that is connected to the parentstructure through an oxygen atom (—O-alkyl). When a cycloalkyl group isconnected to the parent structure through an oxygen atom, the group mayalso be referred to as a cycloalkoxy group. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.A “perhaloalkoxy” intends a perhaloalkyl group attached to the parentstructure through an oxygen, such as the residue —O—CF₃.

“Aryloxy” refers to an aryl group that is connected to the parentstructure through an oxygen atom (—O-aryl), which by way of exampleincludes the residues phenoxy, naphthoxy, and the like. “Substitutedaryloxy” refers to a substituted aryl group connected to the parentstructure through an oxygen atom (—O-substituted aryl).

“Alkylsulfanyl” refers to an alkyl group that is connected to the parentstructure through a sulfur atom (—S-alkyl) and refers to groups —S-alkyland —S-substituted alkyl, which includes the residues —S-cycloalkyl,—S-substituted cycloalkyl, —S-alkenyl, —S-substituted alkenyl,—S-alkynyl, —S-substituted alkynyl, where alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyland substituted cycloalkyl are as defined herein. When a cycloalkylgroup is connected to the parent structure through an sulfur atom, thegroup may also be referred to as a cycloalkylsulfanyl group. By way ofexample, alkylsulfanyl includes —S—CH(CH₃), —S—CH₂CH₃ and the like.

“Alkylsulfinyl” refers to an alkyl group that is connected to the parentstructure through a S(O) moiety and refers to groups —S(O)alkyl and—S(O)substituted alkyl, which includes the residues —S(O)cycloalkyl,—S(O)substituted cycloalkyl, —S(O)alkenyl, —S(O)substituted alkenyl,—S(O)alkynyl, —S(O)substituted alkynyl, where alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyland substituted cycloalkyl are as defined herein. By way of example,alkylsulfinyl includes the residues —S(O)CH(CH₃), —S(O)CH₃,—S(O)cyclopentane and the like.

“Arylsulfinyl” refers to an aryl group that is connected to the parentstructure through a S(O) moiety, which by way of example includes theresidue —S(O)Ph.

“Dialkylamino” refers to the group —NR₂ where each R is an alkyl group.Examples of dialkylamino groups include —N(CH₃)₂, —N(CH₂CH₂CH₂CH₃)₂, andN(CH₃)(CH₂CH₂CH₂CH₃).

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound described herein, such as a compound of Formula (I),(II), (III) or (IV) or other nitroxyl donor of the invention, whichsalts may be derived from a variety of organic and inorganic counterions well known in the art and include, by way of example only, sodium,potassium, calcium, magnesium, ammonium, tetraalkylammonium, and thelike; when the molecule contains a basic functionality, salts of organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. Illustrative saltsinclude, but are not limited, to sulfate, citrate, acetate, chloride,bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, besylate, fumarate,gluconate, glucaronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, andp-toluenesulfonate salts. Accordingly, a salt may be prepared from acompound of any one of the formulae disclosed herein having an acidicfunctional group, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, and lithium; hydroxides of alkaline earth metal suchas calcium and magnesium; hydroxides of other metals, such as aluminumand zinc; ammonia, and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-lower alkyl amines), suchas mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N,-di-lower alkyl-N-(hydroxy lower alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl) amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. A salt may also be prepared from a compound of any one of theformulae disclosed herein having a basic functional group, such as anamino functional group, and a pharmaceutically acceptable inorganic ororganic acid. Suitable acids include hydrogen sulfate, citric acid,acetic acid, hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogeniodide (HI), nitric acid, phosphoric acid, lactic acid, salicylic acid,tartaric acid, ascorbic acid, succinic acid, maleic acid, besylic acid,fumaric acid, gluconic acid, glucaronic acid, formic acid, benzoic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, and p-toluenesulfonic acid.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human.

The term “effective amount” intends such amount of a compound or apharmaceutically acceptable salt thereof, which in combination with itsparameters of efficacy and toxicity, as well as based on the knowledgeof the practicing specialist should be effective in a given therapeuticform. As is understood in the art, an effective amount may be in one ormore doses.

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, including clinical results. For purposesof this invention, beneficial or desired results include but are notlimited to inhibiting and/or suppressing the onset and/or development ofa disease or condition that is responsive to nitroxyl therapy orreducing the severity of such disease or condition, such as reducing thenumber and/or severity of symptoms associated with the disease orcondition, increasing the quality of life of those suffering from thedisease or condition, decreasing the dose of other medications requiredto treat the disease or condition, enhancing the effect of anothermedication an individual is taking for the disease or condition andprolonging survival of individual's having the disease or condition. Thedisease or condition may be a cardiovascular disease or condition, whichincludes, but is not limited to, coronary obstructions, coronary arterydisease (CAD), angina, heart attack, myocardial infarction, high bloodpressure, ischemic cardiomyopathy and infarction, diastolic heartfailure, pulmonary congestion, pulmonary edema, cardiac fibrosis,valvular heart disease, pericardial disease, circulatory congestivestates, peripheral edema, ascites, Chagas' disease, ventricularhypertrophy, heart valve disease, heart failure, including but notlimited to congestive heart failure such as acute congestive heartfailure and acute decompensated heart failure. Related symptoms that maybe alleviated by the methods herein include shortness of breath,fatigue, swollen ankles or legs, angina, loss of appetite, weight gainor loss, associated with aforementioned diseases or disorders. Thedisease or condition may involve ischemia/reperfusion injury.

As used herein, “preventing” refers to reducing the probability ofdeveloping a disorder or condition in an individual who does not have,but is at risk of developing a disorder or condition.”

An individual “at risk” may or may not have a detectable disease orcondition, and may or may not have displayed a detectable disease orcondition prior to the treatment methods described herein. “At risk”denotes that an individual has one or more so-called risk factors, whichare measurable parameters that correlate with development of a diseaseor condition and are known in the art. An individual having one or moreof these risk factors has a higher probability of developing the diseaseor condition than an individual without these risk factor(s).

“Nitroxyl” refers to the species HNO.

As used herein, a compound is a “nitroxyl donor” if it donates nitroxylunder physiological conditions. As used herein, nitroxyl donors of theinvention may alternatively be referred to as “a compound” or “thecompound.” Preferably, the nitroxyl donor is capable of donating aneffective amount of nitroxyl in vivo and has a safety profile indicatingthe compound would be tolerated by an individual in the amount necessaryto achieve a therapeutic effect. One of ordinary skill in the art wouldbe able to determine the safety of administering particular compoundsand dosages to live subjects. One of skill in the art may also determinewhether a compound is a nitroxyl donor by evaluating whether it releasesHNO under physiological conditions. Compounds are easily tested fornitroxyl donation with routine experiments. Although it is impracticalto directly measure whether nitroxyl is donated, several tests areaccepted for determining whether a compound donates nitroxyl. Forexample, the compound of interest can be placed in solution, for examplein water, in a sealed container. After sufficient time fordisassociation has elapsed, such as from several minutes to severalhours, the headspace gas is withdrawn and analyzed to determine itscomposition, such as by gas chromatography and/or mass spectroscopy. Ifthe gas N₂O is formed (which occurs by HNO dimerization), the test ispositive for nitroxyl donation and the compound is a nitroxyl donor. Thelevel of nitroxyl donating ability may be expressed as a percentage of acompound's theoretical maximum. A compound that donates a “significantlevel of nitroxyl” intends a compound that donates 40% or more or 50% ormore of its theoretical maximum amount of nitroxyl. In one variation,the compounds for use herein donate 60% or more of the theoreticalmaximum amount of nitroxyl. In another variation, the compounds for useherein donate 70% or more of the theoretical maximum amount of nitroxyl.In another variation, the compounds for use herein donate 80% or more ofthe theoretical maximum amount of nitroxyl. In another variation, thecompounds for use herein donate 90% or more of the theoretical maximumamount of nitroxyl. In yet another variation, the compounds for useherein donate between about 70% and about 90% of the theoretical maximumamount of nitroxyl. In yet another variation, the compounds for useherein donate between about 85% and about 95% of the theoretical maximumamount of nitroxyl. In yet another variation, the compounds for useherein donate between about 90% and about 95% of the theoretical maximumamount of nitroxyl. Compounds that donate less than 40% or less than 50%of their theoretical amount of nitroxyl are still nitroxyl donors andmay be used in the invention disclosed herein. A compound that donatesless than 50% of the theoretical amount of nitroxyl may be used in themethods described, and may require higher dosing levels as compared tocompounds that donate a significant level of nitroxyl. Nitroxyl donationalso can be detected by exposing the test compound to metmyoglobin(Mb³⁺). Nitroxyl reacts with Mb³⁺ to form an Mb²⁺—NO complex, which canbe detected by changes in the ultraviolet/visible spectrum or byElectron Paramagnetic Resonance (EPR). The Mb²⁺—NO complex has an EPRsignal centered around a g-value of about 2. Nitric oxide, on the otherhand, reacts with Mb³⁺ to form an Mb³⁺—NO complex that is EPR silent.Accordingly, if the candidate compound reacts with Mb³⁺ to form acomplex detectable by common methods such as ultraviolet/visible or EPR,then the test is positive for nitroxyl donation. Testing for nitroxyldonation may be performed at physiologically relevant pH.

A “positive inotrope” as used herein is an agent that causes an increasein myocardial contractile function. Such an agent includes abeta-adrenergic receptor agonist, an inhibitor of phosphodiesteraseactivity, and calcium-sensitizers. Beta-adrenergic receptor agonistsinclude, among others, dopamine, dobutamine, terbutaline, andisoproterenol. Analogs and derivatives of such compounds are alsointended. For example, U.S. Pat. No. 4,663,351 describes a dobutamine,prodrug that can be administered orally. One of ordinary skill in theart would be able to determine if a compound is capable of causingpositive inotropic effects and also additional beta-agonist compounds.In particular embodiments, the beta-receptor agonist is selective forthe beta-1 receptor. However, in other embodiments the beta-agonist isselective for the beta-2 receptor, or is not selective for anyparticular receptor.

Diseases or conditions that are “responsive to nitroxyl therapy” intendsany disease or condition in which administration of a compound thatdonates an effective amount of nitroxyl under physiological conditionstreats and/or prevents the disease or condition, as those terms aredefined herein. A disease or condition whose symptoms are suppressed ordiminished upon administration of nitroxyl donor is a disease orcondition responsive to nitoxyl therapy. Non-limiting examples ofdiseases or conditions that are responsive to nitroxyl therapy includecoronary obstructions, coronary artery disease (CAD), angina, heartattack, myocardial infarction, high blood pressure, ischemiccardiomyopathy and infarction, diastolic heart failure, pulmonarycongestion, pulmonary edema, cardiac fibrosis, valvular heart disease,pericardial disease, circulatory congestive states, peripheral edema,ascites, Chagas' disease, ventricular hypertrophy, heart valve disease,heart failure, including but not limited to congestive heart failuresuch as acute congestive heart failure and acute decompensated heartfailure. Other cardiovascular diseases or conditions are also intended,as are diseases or conditions that implicate ischemia/reperfusioninjury.

N-Hydroxysulfonamide Compounds

The compounds of this invention and for use in the methods describedherein include N-hydroxylsulfonamides that donate nitroxyl underphysiological conditions. Preferably, the compounds predominately donatenitroxyl under physiological conditions, meaning that a compound thatdonates both nitoxyl and nitric oxide under physiological conditionsdonates more nitroxyl than nitric oxide. Preferably, the compounds foruse herein do not donate significant levels of nitric oxide underphysiological conditions. Most preferably, the compounds for use hereindonate significant levels of nitroxyl under physiological conditions.

In one embodiment, the invention embraces a compound of the formula (I):

where R¹ is H; R² is H, aralkyl or heterocyclyl; R³, R⁴, R⁵, R⁶ and R⁷are independently H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl,perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl,substituted heterocycloalkyl, dialkylamino, cycloalkoxy,cycloalkylsulfanyl, arylsulfanyl or arylsulfinyl, provided that: (1) atleast one of R³, R⁴, R⁵, R⁶ and R⁷ is other than H; (2) at least one ofR³, R⁴, R⁵, R⁶ and R⁷ is other than halo; (3) when R³, R⁴, R⁶ and R⁷ areH, R⁵ is other than halo, nitro, cyano, alkyl or alkoxy; (4) when one ofR³ or R⁷ is halo and the R³ or R⁷ that is not halo is H and one of R⁴ orR⁶ is halo and the R⁴ or R⁶ that is not halo is H, R⁵ is other thanhalo; (5) when R³, R⁷ and R⁵ are H and one of R⁴ and R⁶ is H, the R⁴ orR⁶ that is not H is other than N-hydroxysulfonamidyl, perhaloalkyl ornitro; (6) when R⁴, R⁵ and R⁶ are H and one of R³ and R⁷ is H, the R³ orR⁷ that is not H is other than nitro or alkyl; (7) when R³ and R⁷ are H,R⁵ is nitro and one of R⁴ and R⁶ is H, the R⁴ or R⁶ that is not H isother than halo; (8) when R⁴ and R⁶ are nitro and R³ and R⁷ are H, R⁵ isother than dialkylamino; (9) when R⁴ and R⁶ are H and R³ and R⁷ arealkyl, R⁵ is other than alkyl; and (10) when R³ and R⁷ are H and R⁴ andR⁶ are nitro, R⁵ is other than dialkylamino.

In one embodiment, the compound is of the formula (I), where R¹, R², R³,R⁴, R⁵, R⁶ and R⁷ are as defined above, provided that (1) at least oneof R³, R⁴, R⁵, R⁶ and R⁷ is other than H; (2) at least one of R³, R⁴,R⁵, R⁶ and R⁷ is other F; (3) when R³, R⁴, R⁵, R⁶ and R⁷ are H, R⁵ isother than F, Cl, Br, I, NO₂, CN, CH₃ or OCH₃; (4) when one of R³ or R⁷is Cl and the R³ or R⁷ that is not Cl is H and one of R⁴ or R⁶ is Cl andthe R⁴ or R⁶ that is not Cl is H, R⁵ is other than Cl; (5) when R³, R⁷and R⁵ are H and one of R⁴ and R⁶ is H, the R⁴ or R⁶ that is not H isother than SO₂NHOH, CF₃ or NO₂; (6) when R⁴, R⁵ and R⁶ are H and one ofR³ and R⁷ is H, the R³ or R⁷ that is not H is other than NO₂ or CH₃; (7)when R³ and R⁷ are H, R⁵ is NO₂ and one of R⁴ and R⁶ is H, the R⁴ or R⁶that is not H is other than Cl; (8) when R⁴ and R⁶ are nitro and R³ andR⁷ are H, R⁵ is other than a C₁-C₅ dialkylamino; (9) when R⁴ and R⁶ areH and R³ and R⁷ are alkyl, R⁵ is other than CH₃; and (10) when R³ and R⁷are H and R⁴ and R⁶ are nitro, R⁵ is other than a C₁-C₅ dialkylamino.

In another embodiment, the compound is of the formula (I) where R¹ is H;R² is H, aralkyl or heterocyclyl; R⁴, R⁵ and R⁶ are independently H,halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl,cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl,alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl,dialkylamino, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl orarylsulfinyl; at least one of R³ and R⁷ is an electron withdrawing groupor a group that sterically hinders the sulfonyl moiety, provided that:(1) when one of R³ or R⁷ is halo and the R³ or R⁷ that is not halo is Hand one of R⁴ or R⁶ is halo and the R⁴ or R⁶ that is not halo is H, R⁵is other than halo and (2) when R⁴, R⁵ and R⁶ are H and one of R³ and R⁷is H, the R³ or R⁷ that is not H is other than nitro or alkyl. In onevariation, at least one of R³ or R⁷ is an electron withdrawing group. Inanother variation, both R³ and R⁷ are electron withdrawing groups. Inanother variation, at least one of R³ or R⁷ is a group that stericallyhinders the sulfonyl moiety of compound (I). In one variation, at leastone of R³ or R⁷ is a branched alkyl group, such as i-propyl or t-butyl.In another variation, both R³ and R⁷ are alkyl groups provided that oneof the alkyl groups is a branched alkyl group, such as when both groupsare isopropyl or when one group is ethyl and the other is sec-butyl. Inone variation, one of R³ and R⁷ is an electron withdrawing group and theR³ or R⁷ that is not an electron withdrawing group is an alkyl group,which may be a branched alkyl group such as isopropyl.

Also embraced is a compound of the formula (I) where R¹ is H; R² is H,benzyl or tetrahydropyran-2-yl; R³, R⁴, R⁵, R⁶ and R⁷ are independentlyselected from the group consisting of H, Cl, F, I, Br, SO₂CH₃, SO₂NHOH,CF₃, NO₂, phenyl, CN, OCH₃, OCF₃, t-Bu, O-iPr, 4-nitrophenyloxy(OPh4-NO₂), propane-2-thiyl (SCH(CH₃)₂), propane-2-sulfinyl(S(O)CH(CH₃)₂), morpholino, N-methyl-piperazino, dimethylamino,piperidino, cyclohexyloxy, cyclopentylsulfanyl, phenylsulfanyl andphenylsulfinyl, provided that: (1) at least one of R³, R⁴, R⁵, R⁶ and R⁷is other than H; (2) at least one of R³, R⁴, R⁵, R⁶ and R⁷ is other thanF; (3) when R³, R⁴, R⁶ and R⁷ are H, R⁵ is other than F, Cl, Br, I, NO₂,CN or OCH₃; (4) when one of R³ or R⁷ is Cl and the R³ or R⁷ that is notCl is H and one of R⁴ or R⁶ is Cl and the R⁴ or R⁶ that is not Cl is H,R⁵ is other than Cl; (5) when R³, R⁷ and R⁵ are H and one of R⁴ and R⁶is H, the R⁴ or R⁶ that is not H is other than SO₂NHOH, CF₃ or NO₂; (6)when R⁴, R⁵ and R⁶ are H and one of R³ and R⁷ is H, the R³ or R⁷ that isnot H is other than NO₂; and (7) when R³ and R⁷ are H, R⁵ is NO₂ and oneof R⁴ and R⁶ is H, the R⁴ or R⁶ that is not H is other than Cl.

For any of the variations described for formula (I), included arevariations of formula (I) where R¹ is H and R² is H, benzyl ortetrahydropyran-2-yl. In one variation, the compound is of the formula(I) where at least two of R³, R⁴, R⁵, R⁶ and R⁷ are halo, such as thecompound of formula (I) where R⁵ is halo (such as F or Br) and one of R³and R⁷ is halo (such as Br, or Cl) or where both R³ and R⁷ or both R³and R⁴ are halo (such as when both are Cl or both are F or one is Cl andone is F), and the remaining substituents are as described in thevariations above. In one variation, the compound is of the formula (I)where at least one of R³, R⁴, R⁵, R⁶ and R⁷ is —S(O)Oalkyl, such as whenone of R³ or R⁷ is —S(O)OCH₃. In one variation, the compound is of theformula (I) where at least one of R³, R⁵ and R⁷ is a perhaloalkyl, suchas when R³ is CF₃ or when R³ and R⁵ are CF₃. In one variation, thecompound is of the formula (I) where R⁵ is CF₃ and at least one of R³and R⁷ is other than H, such as when R⁵ is CF₃ and R³ is NO₂ or Cl. Inone variation, the compound is of the formula (I) where at least one ofR³, R⁴, R⁵, R⁶ and R⁷ is an aryl group, such as when at least one of R³and R⁷ is an aryl group, such as phenyl. In one variation, the compoundis of the formula (I) where at least one of R³, R⁴, R⁵, R⁶ and R⁷ is aheterocyclyl group, such as when at least one of R³, R⁵ and R⁷ is aheterocyclyl group or substituted heterocylco group, such as morpholino,N-methyl, piperizino and piperidino. In one variation, the compound isof the formula (I) where at least one of R³, R⁴, R⁵, R⁶ and R⁷ is acycloaloxy or cycloalkylsulfanyl group such as when at least one of R³,R⁵ and R⁷ is a cyclohexyloxy, cyclopentyloxy, cyclohexylsulfanyl orcyclopentylsulfanyl group. In one variation, the compound is of theformula (I) where at least one of R³, R⁴, R⁵, R⁶ and R⁷ is anarylsulfanyl or arylsulfinyl group, such as when at least one of R³, R⁵and R⁷ is a phenylsulfanyl or phenylsulfinyl group.

Representative compounds of the formula (I) include, but are not limitedto, the compounds listed in Table 1.

TABLE 1 Representative Compounds of Formula (I):

In one embodiment, the nitroxyl donating compound is a compound of theformula (II):

where R¹ is H; R² is H, aralkyl or heterocyclyl; m and n areindependently an integer from 0 to 1; x is an integer from 0 to 4; y isan integer from 0 to 3; A is a cycloalkyl, heterocycloalkyl, aromatic orheteroaromatic ring containing ring moieties Q¹, Q², Q³ and Q⁴, whichare taken together with the carbons at positions a and a′ to form ringA; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ringcontaining ring moieties Q⁵, Q⁶, Q⁷ and Q⁸, which are taken togetherwith the carbons at positions a and a′ to form ring B; Q¹, Q², Q³, Q⁴,Q⁵, Q⁶, Q⁷ and Q⁸ are independently selected from the group consistingof C, CH₂, CH, N, NR¹⁰, O and S, provided that either (1) when rings Aand B form naphthalene, x is an integer from 1 to 3 or y is an integerfrom 2 to 4 or R⁸ is other than Cl or (2) at least one of Q¹, Q², Q³,Q⁴, Q⁵, Q⁶, Q⁷ and Q⁸ is N, NR¹⁰, O or S; each R⁸ and R⁹ isindependently selected from the group consisting of halo, alkylsulfonyl,N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl, cyano, alkoxy,perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl, alkylsulfinyl,heterocycloalkyl, substituted heterocycloalkyl, dialkylamino, NH₂, OH,C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH₂, NHC(O)alkylC(O)alkyl,NHC(O)alkenylC(O)OH, NHC(O)NH₂, OalkylC(O)Oalkyl, NHC(O)alkyl,C(═N—OH)NH₂, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl, andarylsulfinyl; and R¹⁰ is H, alkyl, acyl, or sulfonyl.

In one variation, the compound is of the formula (II) where each R⁸ andR⁹ is independently selected from the group consisting of Cl, F, I, Br,SO₂CH₃, SO₂NHOH, CF₃, CH₃, NO₂, phenyl, CN, OCH₃, OCF₃, t-Bu, O-iPr,4-nitrophenyloxy (OPh4-NO₂), propane-2-thiyl (SCH(CH₃)₂),propane-2-sulfinyl (S(O)CH(CH₃)₂), morpholino, N-methyl-piperazino,dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl,phenylsulfanyl and phenylsulfinyl; and R¹⁰ is H, alkyl, acyl orsulfonyl, provided that when rings A and B form naphthalene, x is aninteger from 1 to 3 or y is an integer from 2 to 4.

For any of the variations described for formula (II), included arevariations of formula (II) where R¹ is H and R² is H, benzyl ortetrahydropyran-2-yl. In one variation, A and B form a benzofuran orbenzothiophene or benzoimidazole or N-alkylbenzoimidazole (such asN-methylbenzoimidazole) or N-acylbenzoimidazole (such asN—C(O)CH₃benzoimidazole) or benzothiazole or benzooxazole. In onevariation, A and B form a benzofuran. In one variation, A and B form abenzofuran and x and y are 0. In one variation, A and B form abenzothiophene. In one variation, A and B form a benzothiophene, y is 0and x is 1. In one variation, A and B form naphthyl and x is 0, y is 1and R⁸ is a halo group. In one variation, ring A is phenyl and ring B isa heteroaryl group, such as when rings A and B form quinoline and ring Bis the nitrogen containing ring. The invention also embraces compoundsaccording to any of the variations for formula (II) where y is 0, x is 1and R⁹ is a halo, alkyl or perhaloalkyl group. The invention alsoembraces compounds according to any of the variations for formula (II)where x is 2 and y is 0.

Representative compounds of the formula (II) include, but are notlimited to, the compounds listed in Table 2.

TABLE 2 Representative Compounds of Formula (II):

In another embodiment, the nitroxyl donating compound is a compound ofthe formula (III):

where R¹ is H; R² is H, aralkyl or heterocyclyl; n is an integer from 0to 1; b is an integer from 0 to 4; C is a heteroaromatic ring containingring moieties Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³ and Q¹⁴ that are independentlyselected from the group consisting of C, CH₂, CH, N, NR¹⁰, O and S,provided that at least one of Q⁹, Q¹⁰, Q¹¹, Q¹², Q¹³, and Q¹⁴ is N,NR¹⁰, O or S; each R⁸ is independently selected from the groupconsisting of halo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl,nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy,alkylsulfanyl, alkylsulfinyl, heterocycloalkyl, substitutedheterocycloalkyl, dialkylamino, NH₂, OH, C(O)OH, C(O)Oalkyl,NHC(O)alkylC(O)OH, C(O)NH₂, NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH,NHC(O)NH₂, OalkylC(O)Oalkyl, NHC(O)alkyl, C(═N—OH)NH₂, cycloalkoxy,cycloalkylsulfanyl, arylsulfanyl, and arylsulfinyl; and R¹⁰ is H, alkyl,acyl or sulfonyl.

In one variation, the compound is of the formula (III) and each R⁸ isindependently selected from the group consisting of Cl, F, I, Br,SO₂CH₃, SO₂NHOH, CF₃, CH₃, NO₂, phenyl, CN, OCH₃, OCF₃, t-Bu, O-iPr,4-nitrophenyloxy (OPh4-NO₂), propane-2-thiyl (SCH(CH₃)₂),propane-2-sulfinyl (S(O)CH(CH₃)₂), morpholino, N-methyl-piperazino,dimethylamino, piperidino, cyclohexyloxy, cyclopentylsulfanyl,phenylsulfanyl and phenylsulfanyl. In another variation, the compound isof the formula (III) and each R⁸ is independently selected from thegroup consisting of F, Br, Cl, CF₃, phenyl, methyl, SO₂NHOH, morpholino,piperidino, 4-methyl-piperazino.

For any of the variations described for formula (III), included arevariations of formula (III) where R¹ is H and R² is H, benzyl ortetrahydropyran-2-yl. In one variation, n is 0 and C is a thiophene orisoxazole or pyrazole or pyrrole or imidazole or furan or thiazole ortriazole or N-methylimidazole or thiadiazole. In another variation, n is0 and C is a thiophene or isoxazole or pyrazole or pyrrole or imidazoleor furan or thiazole or triazole or N-methylimidazole or thiadiazole andeither (1) b is 1 and R⁸ is either a halo (such as Cl or Br), nitro,alkyl (such as methyl), cyano or (2) b is 2 and each R⁸ is a halo group.In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridine.In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridineand b is either 0 or 1, and where R⁸ is halo or heterocyclyl if b is 1.In one variation, n is 1 and C is a pyrimidine or pyrazine or pyridine,b is 1, and R⁸ is chloro or morpholino or piperidino orN-methylpiperizino. In one variation, C is thiophene and b is 1. In onevariation, C is thiophene, b is 1 and R⁸ is halo. In one variation, C isthiophene and b is 0.

Representative compounds of the formula (III) include, but are notlimited to, the compounds listed in Table 3.

TABLE 3 Representative compounds of the formula (III).

In one embodiment, the nitroxyl donating compound is of the formula(IV):

where R¹ is H; R² is H, aralkyl or heterocyclyl; T is alkyl orsubstituted alkyl (which includes a cycloalkyl or substitutedcycloalkyl) and Z is an electron withdrawing group. In one variation, Tis a C₁ to C₆ branched alkyl, such as isopropyl, t-butyl or sec-butyl.In another variation, T is a C₁ to C₆ branched alkyl, such as isopropyl,t-butyl or sec-butyl and Z is selected from the group consisting of F,Cl, Br, I, —CN, —CF₃, —NO₂, —SH, —C(O)H, —C(O)alkyl, —C(O)Oalkyl,—C(O)OH, —C(O)Cl, —S(O)₂OH, —S(O)₂NHOH, —NH₃. For any of the variationsdescribed for formula (IV), included are variations of formula (IV)where R¹ is H and R² is H, benzyl or tetrahydropyran-2-yl.

Representative compounds of the formula (IV) include, but are notlimited to, the compounds listed in Table 4.

TABLE 4 Representative compounds of the formula (IV).

Compounds for Use in the Methods

The methods described employ N-hydroxysulfonamides that donate aneffective amount of nitroxyl under physiological conditions. Any of themethods may employ an N-hydroxylsulfonamide compound described aboveunder “N-Hydroxysulfonamide Compounds.” The methods may also employother N-hydroxysulfonamides that donate an effective amount of nitroxylunder physiological conditions, including those described by theformulae below:

where R¹ is H; R² is H; m and n are independently an integer from 0 to2; x and b are independently an integer from 0 to 4; y is an integerfrom 0 to 3; T is an alkyl or substituted alkyl; Z is an electronwithdrawing group; R³, R⁴, R⁵, R⁶ and R⁷ are independently selected fromthe group consisting of H, halo, alkylsulfonyl, N-hydroxylsulfonamidyl,perhaloalkyl, nitro, aryl, cyano, alkoxy, perhaloalkoxy, alkyl,substituted aryloxy, alkylsulfanyl, alkylsulfinyl, heterocycloalkyl,substituted heterocycloalkyl, dialkylamino, cycloalkoxy,cycloalkylsulfanyl, arylsulfanyl and arylsulfinyl, provided thatprovided that: (1) at least one of R³, R⁴, R⁵, R⁶ and R⁷ is other thanH; each R⁸ and R⁹ is independently selected from the group consisting ofhalo, alkylsulfonyl, N-hydroxylsulfonamidyl, perhaloalkyl, nitro, aryl,cyano, alkoxy, perhaloalkoxy, alkyl, substituted aryloxy, alkylsulfanyl,alkylsulfinyl, heterocycloalkyl, substituted heterocycloalkyl,dialkylamino, NH₂, OH, C(O)OH, C(O)Oalkyl, NHC(O)alkylC(O)OH, C(O)NH₂,NHC(O)alkylC(O)alkyl, NHC(O)alkenylC(O)OH, NHC(O)NH₂, OalkylC(O)Oalkyl,NHC(O)alkyl, C(═N—OH)NH₂, cycloalkoxy, cycloalkylsulfanyl, arylsulfanyl,and arylsulfinyl; A is a cycloalkyl, heterocycloalkyl, aromatic orheteroaromatic ring containing ring moieties Q¹, Q², Q³ and Q⁴, whichare taken together with the carbons at positions a and a′ to form ringA; B is a cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic ringcontaining ring moieties Q⁵, Q⁶, Q⁷ and Q⁸, which are taken togetherwith the carbons at positions a and a′ to form ring B; Q¹, Q², Q³, Q⁴,Q⁵, Q⁶, Q⁷ and Q⁸ are independently selected from the group consistingof C, CH₂, CH, N, NR¹⁰, O and S; C is a heteroaromatic ring containingring moieties Q⁹, Q¹¹, Q¹², Q¹³ and Q¹⁴ that are independently selectedfrom the group consisting of C, CH₂, CH, N, NR¹⁰, O and S; and R¹⁰ is H,alkyl, acyl or sulfonyl.

Any of the methods may also utilize any of the specificN-hydroxylsulfonamide compounds listed in Tables 1-4. The methods mayalso employ any of the compounds listed Table 5. The compounds of Table5 have been described in the literature (See, e.g., Mincione, F.;Menabuoni, L.; Briganti, F.; Mincione, G.; Scozzafava, A.; Supuran, C.T. J. Enzyme Inhibition 1998, 13, 267-284 and Scozzafava, A.; Supuran,C. T. J. Med. Chem. 2000, 43, 3677-3687) but have not been proposed foruse in the treatment or prevention of diseases or conditions that areresponsive to nitroxyl therapy, such as use in the treatment of heartfailure, including acute congestive heart failure, orischemia/reperfusion injury. Compounds that donate nitroxyl but do notdonate significant levels of nitroxyl may be used in the methods, butwill generally require a higher dosing to produce the same physiologicaleffect as compared to compounds that donate significant levels ofnitroxyl.

TABLE 5 Additional Compounds for use in the Methods.

n = 1-3

n = 1 or 2

n = 4-7

For any of the compounds of the invention, such as the compounds offormula (I), (II), (III) or (IV) or other compounds for use in themethods described herein, recitation or depiction of the parent compoundintends and includes all salts, solvates, hydrates, polymorphs, orprodrugs thereof, where applicable. As such, all salts, such aspharmaceutically acceptable salts, solvates, hydrates, polymorphs andprodrugs of a compound are embraced by the invention and describedherein the same as if each and every salts, solvate, hydrate, polymorph,or prodrug were specifically and individually listed.

For all compounds disclosed herein, where applicable due to the presenceof a stereocenter, the compound is intended to embrace all possiblestereoisomers of the compound depicted or described. Compositionscomprising a compound with at least one stereocenter are also embracedby the invention, and includes racemic mixtures or mixtures containingan enantiomeric excess of one enantiomer or single diastereomers ordiastereomeric mixtures. All such isomeric forms of these compounds areexpressly included herein the same as if each and every isomeric formwere specifically and individually listed. The compounds herein may alsocontain linkages (e.g., carbon-carbon bonds) wherein bond rotation isrestricted about that particular linkage, e.g. restriction resultingfrom the presence of a ring or double bond. Accordingly, all cis/transand E/Z isomers are also expressly included in the present invention.The compounds herein may also be represented in multiple tautomericforms, in such instances, the invention expressly includes alltautomeric forms of the compounds described herein, even though only asingle tautomeric form may be represented. Also embraced arecompositions of substantially pure compound. A composition ofsubstantially pure compound means that the composition contains no morethan 25%, or no more than 15%, or no more than 10%, or no more than 5%,or no more than 3% impurity, or no more than 1% impurity, such as adifferent biologically active compound, which may include a differentstereochemical form of the compound if the composition contains asubstantially pure single isomer.

The compounds of the invention can be made according to the generalmethods described in Schemes A-C or by procedures known in the art.Starting materials for the reactions are either commercially availableor may be prepare by known procedures or obvious modifications thereof.For example, many of the starting materials are available fromcommercial suppliers such as Sigma-Aldrich. Others may be prepared byprocedures or obvious modifications thereof described in standardreference texts such as March's Advanced Organic Chemistry, (John Wileyand Sons) and Larock's Comprehensive Organic Transformations (VCHPublishers Inc.).

In Scheme A, a solution of hydroxylamine hydrochloride in water ischilled to 0° C. A solution of potassium carbonate in water is addeddropwise, maintaining an internal reaction temperature between about 5°C. and about 15° C. The reaction mixture is stirred for about 15minutes, whereupon tetrahydrofuran (THF) and methanol (MeOH) are added.Compound A1 (where R is an alkyl, aryl or heterocyclyl group) is addedportionwise maintaining a temperature below about 15° C. and thereaction mixture is stirred at ambient temperature until completeconsumption of the sulfonyl chloride is observed by thin layerchromatography (TLC). The resulting suspension is concentrated to removeany volatiles and the aqueous suspension is extracted with diethylether. The organic portion is dried over magnesium sulfate, filtered andconcentrated in vacuo to yield the crude N-hydroxy sulphonamide A2.Purification may be achieved by conventional methods, such aschromatography, filtration, crystallization and the like.

N-Benzyloxysulfonamides are chemical intermediates that are used asprotected N-hydroxysulfonamides for the further modification of the Rmoiety of compound B2. In Scheme B, a suspension ofO-benzylhydroxylamine hydrochloride B1 in methanol and water is added toa chilled solution of potassium carbonate in water, maintaining aninternal reaction temperature below about 10° C. The reaction mixture isstirred for about 5 minutes, whereupon THF and A1 (where R is an alkyl,aryl or heterocyclyl group) are added. The reaction mixture is stirredat ambient temperature until complete consumption of the sulfonylchloride was observed by TLC. The resulting suspension is concentratedin vacuo to remove any volatiles, and the aqueous suspension wasextracted with diethyl ether. The organic layer was dried over sodiumsulfate, filtered and concentrated in vacuo to yield the crude targetcompound B2. Purification may be achieved by conventional methods, suchas chromatography, filtration, crystallization and the like. Thereaction product B2 may be deprotected by removing the benzyl group. Forinstance, a suspension of 10% palladium on charcoal may be added to asuspension of B2 in methanol. The reaction mixture is stirred under ahydrogen atmosphere at ambient temperature and atmospheric pressureovernight. The reaction mixture is filtered through microfibre glasspaper. The resulting filtrate is concentrated in vacuo, and the residuepurified by conventional methods to yield the correspondingN-hydroxylsulfonamide.

N-(tetrahydro-pyran-2-yloxy)sulfonamides are chemical intermediates thatare used as protected N-hydroxysulfonamides for the further modificationof the R moiety of compound C2. In Scheme C, to a solution of Cl inwater at 0° C. is added a solution of potassium carbonate in waterdropwise, maintaining an internal reaction temperature below about 10°C. After about 15 minutes, methanol and THF are added dropwise, followedby A1 portionwise. The reaction mixture is stirred at ambienttemperature until complete consumption of the sulfonyl chloride isobserved by TLC. The resulting suspension was concentrated to remove anyvolatiles and the aqueous suspension was extracted with diethyl ether.The organic portion is dried over sodium sulfate, filtered andconcentrated in vacuo to yield the crude target compound C2.Purification may be achieved by conventional methods, such aschromatography, filtration, crystallization and the like. Deprotectionof C2 to yield the corresponding N-hydroxylsulfonamide may be carriedout according to methods known in the art.

Particular examples of compounds made according to the general syntheticprocedures of Schemes A-C are found in Examples 1-3.

Methods of Using the Compounds and Compositions

The compounds and compositions herein may be used to treat and/orprevent the onset and/or development of a disease or condition that isresponsive to nitroxyl therapy.

The invention embraces methods of administering to an individual(including an individual identified as in need of such treatment) aneffective amount of a compound to produce a desired effect. Identifyinga subject in need of such treatment can be in the judgment of aphysician, clinical staff, emergency response personnel or other healthcare professional and can be subjective (e.g. opinion) or objective(e.g. measurable by a test or diagnostic method).

One embodiment provides a method of modulating (including increasing) invivo nitroxyl levels in an individual in need thereof, the methodcomprising administering to the individual a compound that donatesnitroxyl under physiological conditions or a pharmaceutically acceptablesalt thereof. An individual is in need of nitroxyl modulation if theyhave or are suspected of having or are at risk of having or developing adisease or condition that is responsive to nitroxyl therapy.

Particular diseases or conditions embraced by the methods of theinvention include cardiovascular diseases such as heart failure orconditions and diseases or conditions that implicate or may implicateischemia/reperfusion injury. These methods are described in more detailbelow.

Compositions comprising a nitroxyl-donating compound of the inventionare embraced by the invention. However, the methods described may usemore than one nitroxyl donating compound; for example, the methods mayemploy Angeli's salt and an N-hydroxysulfonamide of the presentinvention or two or more N-hydroxysulfonamides of the present invention,which may be administered together or sequentially.

Cardiovascular Diseases

Provided herein are methods of treating cardiovascular diseases such asheart failure by administering an effective amount of at least onenitroxyl donating compound to an individual in need thereof. Alsoprovided are methods of administering a therapeutically effective doseof at least one nitroxyl donating compound in combination with at leastone other positive inotropic agent to an individual in need thereof.Further provided are methods of administering a therapeuticallyeffective amount of at least one nitroxyl donating compound to anindividual who is receiving beta-antagonist therapy and who isexperiencing heart failure. Methods are provided herein foradministering compounds of the invention in combination withbeta-adrenergic agonists to treat heart failure. Such agonists includedopamine, dobutamine, and isoproterenol, and analogs and derivatives ofsuch compounds. Also provided are methods of administering nitroxyldonors to individuals receiving treatment with beta-antagonizing agentssuch as propranolol, metoprolol, bisoprolol, bucindolol, and carvedilol.Further, methods are provided herein for treating specificclassifications of heart failure, such as Class III heart failure andacute heart failure.

Also embraced by the invention is a method of treating congestive heartfailure (CHF), including acute congestive heart failure, byadministering an effective amount at least one nitroxyl donatingcompound to an individual in need thereof, which individual may beexperiencing heart failure. Also disclosed is a method of treating CHFby administering an effective amount of at least one nitroxyl donatingcompound in combination with an effective amount of at least one otherpositive inotropic agent to an individual in need thereof, whichindividual may be experiencing heart failure. In one variation, theother positive inotrope is a beta-adrenergic agonist, such asdobutamine. The combined administration of a nitroxyl donor and at leastone other positive inotropic agent comprises administering the nitroxyldonor either sequentially with the other positive inotropic agent forexample, the treatment with one agent first and then the second agent,or administering both agents at substantially the same time, whereinthere is an overlap in performing the administration. With sequentialadministration, an individual is exposed to the agents at differenttimes, so long as some amount of the first agent, which is sufficient tobe therapeutically effective in combination with the second agent,remains in the subject when the other agent is administered. Treatmentwith both agents at the same time can involve administration of theagents in the same dose, such as a physically mixed dose, or in separatedoses administered at the same time.

In particular an embodiment, a nitroxyl donor is administered to anindividual experiencing heart failure that is receiving beta-antagonisttherapy. A beta-antagonist (also known as a beta-blocker) includes anycompound that effectively acts as an antagonist at a subject'sbeta-adrenergic receptors, and provides desired therapeutic orpharmaceutical results, such as diminished vascular tone and/or heartrate. A subject who is receiving beta-antagonist therapy is any subjectto whom a beta-antagonist has been administered, and in whom thebeta-antagonist continues to act as an antagonist at the subject'sbeta-adrenergic receptors. In particular embodiments a determination ofwhether a subject is receiving beta-blocking therapy is made byexamination of the subject's medical history. In other embodiments thesubject is screened for the presence of beta-blocking agents by chemicaltests, such as high-speed liquid chromatography as described in Theviset al., Biomed. Chromatogr., 15:393-402 (2001).

The administration of a nitroxyl donating compound either alone, incombination with a positive inotropic agent, or to a subject receivingbeta-antagonist therapy, is used to treat heart failure of allclassifications. In particular embodiments a nitroxyl donating compoundis used to treat early-stage chronic heart failure, such as Class IIheart failure. In other embodiments a nitroxyl donating compound is usedin combination with a positive inotropic agent, such as isoproterenol totreat Class IV heart failure. In still other embodiments a nitroxyldonating compound is used in combination with another positive inotropicagent, such as isoproterenol to treat acute heart failure. In someembodiments, when a nitroxyl donor is used to treat early stage heartfailure, the dose administered is lower than that used to treat acuteheart failure. In other embodiments the dose is the same as is used totreat acute heart failure.

Ischemia/Reperfusion Injury

The invention embraces methods of treating or preventing or protectingagainst ischemia/reperfusion injury. In particular, compounds of theinvention are beneficial for individuals at risk for an ischemic event.Thus, provided herein is a method of preventing or reducing the injuryassociated with ischemia/reperfusion by administering an effectiveamount of at least one nitroxyl donating compound to an individual,preferably prior to the onset of ischemia. A compound of the inventionmay be administered to an individual after ischemia but beforereperfusion. A compound of the invention may also be administered afterischemia/reperfusion, but where the administration protects againstfurther injury. Also provided is a method in which the individual isdemonstrated to be at risk for an ischemic event. Also disclosed is amethod of administering a nitroxyl donating compound to an organ that isto be transplanted in an amount effective to reduce ischemia/reperfusioninjury to the tissues of the organ upon reperfusion in the recipient ofthe transplanted organ.

Nitroxyl donors of the invention may thus be used in methods ofpreventing or reducing injury associated with futureischemia/reperfusion. For example, administration of a nitroxyl donorprior to the onset of ischemia may reduce tissue necrosis (the size ofinfarct) in at-risk tissues. In live subjects this may be accomplishedby administering an effective amount of a nitroxyl donating compound toan individual prior to the onset of ischemia. In organs to betransplanted this is accomplished by contacting the organ with anitroxyl donor prior to reperfusion of the organ in the transplantrecipient. Compositions comprising more than one nitroxyl-donatingcompound also could be used in the methods described, for example,Angeli's salt and an N-hydroxysulfonamide of the present invention ortwo or more N-hydroxysulfonamides of the present invention. Thenitroxyl-donating compound also can be used in combination with otherclasses of therapeutic agents that are designed to minimize ischemicinjury, such as beta blockers, calcium channel blockers, anti-platelettherapy or other interventions for protecting the myocardium inindividuals with coronary artery disease.

One method of administering a nitroxyl donor to live subjects includesadministration of the nitroxyl-donating compound prior to the onset ofischemia. This refers only to the onset of each instance of ischemia andwould not preclude performance of the method with subjects who have hadprior ischemic events, i.e., the method, also contemplatesadministration of nitroxyl-donating compounds to a subject who has hadan ischemic event in the past.

Individuals can be selected who are at risk of a first or subsequentischemic event. Examples include individuals with knownhypercholesterolemia, EKG changes associated with risk of ischemia,sedentary lifestyle, angiographic evidence of partial coronary arteryobstruction, echocardiographic evidence of myocardial damage, or anyother evidence of a risk for a future or additional ischemic event (forexample a myocardial ischemic event, such as a myocardial infarction(MI), or a neurovascular ischemia such as a cerebrovascular accidentCVA). In particular examples of the methods, individuals are selectedfor treatment who are at, risk of future ischemia, but who have nopresent evidence of ischemia (such as electrocardiographic changesassociated with ischemia (for example, peaked or inverted T-waves or STsegment elevations or depression in an appropriate clinical context),elevated CKMB, or clinical evidence of ischemia such as crushingsub-sternal chest pain or arm pain, shortness of breath and/ordiaphoresis). The nitroxyl-donating compound also could be administeredprior to procedures in which myocardial ischemia may occur, for examplean angioplasty or surgery (such as a coronary artery bypass graftsurgery). Also embraced is a method of administering a nitroxyl-donatingcompound to an individual at demonstrated risk for an ischemic event.The selection of an individual with such a status could be performed bya variety of methods, some of which are noted above. For example, anindividual with one of more of an abnormal EKG not associated withactive ischemia, prior history of myocardial infarction, elevated serumcholesterol, etc., would be at risk for an ischemic event. Thus, anat-risk individual could be selected by physical testing or elicitingthe potential subject's medical history to determine whether the subjecthas any indications of risk for an ischemic event. If risk isdemonstrated based on the indications discussed above, or any otherindications that one skilled in the art would appreciate, then theindividual would be considered at demonstrated risk for an ischemicevent.

Ischemia/reperfusion may damage tissues other than those of themyocardium and the invention embraces methods of treating or preventingsuch damage. In one variation, the method finds use in reducing injuryfrom ishemia/reperfusion in the tissue of the brain, liver, gut, kidney,bowel, or in any other tissue. The methods preferably involveadministration of a nitroxyl donor to an individual at risk for suchinjury. Selecting a person at risk for non-myocardial ischemia couldinclude a determination of the indicators used to assess risk formyocardial ischemia. However, other factors may indicate a risk forischemia/reperfusion in other tissues. For example, surgery patientsoften experience surgery related ischemia. Thus, individuals scheduledfor surgery could be considered at risk for an ischemic event. Thefollowing risk factors for stroke (or a subset of these risk factors)would demonstrate a subject's risk for ischemia of brain tissue:hypertension, cigarette smoking, carotid artery stenosis, physicalinactivity, diabetes mellitus, hyperlipidemia, transient ischemicattack, atrial fibrillation, coronary artery disease, congestive heartfailure, past myocardial infarction, left ventricular dysfunction withmural thrombus, and mitral stenosis. Ingall, “Preventing ischemicstroke: current approaches to primary and secondary prevention,”Postgrad. Med., 107(6):34-50 (2000). Further, complications of untreatedinfectious diarrhea in the elderly can include myocardial, renal,cerebrovascular and intestinal ischemia. Slotwiner-Nie & Brandt,“Infectious diarrhea in the elderly,” Gastroenterol, Clin. N. Am.,30(3):625-635 (2001). Alternatively, individuals could be selected basedon risk factors for ischemic bowel, kidney or liver disease. Forexample, treatment would be initiated in elderly subjects at risk ofhypotensive episodes (such as surgical blood loss). Thus, subjectspresenting with such an indication would be considered at risk for anischemic event. Also embraced is a method of administering a nitroxyldonating compound of the invention to an individual who has any one ormore of the conditions listed herein, such as diabetes mellitus orhypertension. Other conditions that may result in ischemia such ascerebral arteriovenous malformation would be considered to demonstraterisk for an ischemic event.

The method of administering nitroxyl to organs to be transplantedincludes administration of nitroxyl prior to removal of the organ fromthe donor, for example through the perfusion cannulas used in the organremoval process. If the organ donor is a live donor, for example akidney donor, the nitroxyl donor can be administered to the organ donoras described above for a subject at risk for an ischemic event. In othercases the nitroxyl donor can be administered by storing the organ in asolution comprising the nitroxyl donor. For example, the nitroxyl donorcan be included in the organ preservation solution, such as Universityof Wisconsin “UW” solution, which is a solution comprising hydroxyethylstarch substantially free of ethylene glycol, ethylene chlorohydrin andacetone (see U.S. Pat. No. 4,798,824).

Pharmaceutical Composition, Dosage Forms and Treatment Regimens

Also included are pharmaceutically acceptable compositions comprising acompound of the invention or pharmaceutically acceptable salt thereofand any of the methods may employ the compounds of the invention as apharmaceutically acceptable composition. A pharmaceutically acceptablecomposition includes one or more of the compounds of the inventiontogether with a pharmaceutically acceptable carrier. The pharmaceuticalcompositions of the invention include those suitable for oral, rectal,nasal, topical (including buccal and sublingual), vaginal or parenteral(including subcutaneous, intramuscular, intravenous and intradermal)administration.

The compounds or compositions may be prepared as any available dosageform. Unit dosage forms are also intended, which includes discrete unitsof the compound or composition such as capsules, sachets or tablets eachcontaining a predetermined amount of the compound; as a powder orgranules; as a solution or a suspension in an aqueous liquid or anon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion, or packed in liposomes and as a bolus,etc.

A tablet containing the compound or composition may be made bycompression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with a binder, lubricant, inertdiluerit, preservative, surface-active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered compound moistened with an inert liquid diluent. The tabletsoptionally may be coated or scored and may be formulated so as toprovide slow or controlled release of the active ingredient therein.Methods of formulating such slow or controlled release compositions ofpharmaceutically active ingredients, such as those herein and othercompounds known in the art, are known in the art and described inseveral issued US patents, some of which include, but are not limitedto, U.S. Pat. Nos. 4,369,174 and 4,842,866, and references citedtherein. Coatings can be used for delivery of compounds to the intestine(see, e.g., U.S. Pat. Nos. 6,638,534, 5,217,720 and 6,569,457, andreferences cited therein). A skilled artisan will recognize that inaddition to tablets, other dosage forms can be formulated to provideslow or controlled release of the active ingredient. Such dosage formsinclude, but are not limited to, capsules, granulations and gel-caps.

Compositions suitable for topical administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use.

Extemporaneous injection solutions and suspensions may be prepared fromsterile powders, granules and tablets.

Administration of the compounds or compositions to an individual mayinvolve systemic exposure or may be local administration, such as when acompound or composition is to be administered at the site of interest.Various techniques can be used for providing the subject compositions atthe site of interest, such as via injection, use of catheters, trocars,projectiles, pluronic gel, stems, sustained drug release polymers orother device which provides for internal access. Where an organ ortissue is accessible because of removal from the patient, such organ ortissue may be bathed in a medium containing the subject compositions,the subject compositions may be painted onto the organ, or may beapplied in any convenient way. The methods of the invention embraceadministration of the compounds to an organ to be donated (such as toprevent ischemia/reperfusion injury). Accordingly, organs that areremoved from one individual for transplant into another individual maybe bathed in a medium containing or otherwise exposed to a compound orcomposition as described herein.

The compounds of the invention, such as those of the formulae herein,may be administered in any suitable dosage amount, which may includedosage levels of about 0.0001 to 4.0 grams once per day (or multipledoses per day in divided doses) for adults. Thus, in certain embodimentsof this invention, a compound herein is administered at a dosage of anydosage range in which the low end of the range is any amount between 0.1mg/day and 400 mg/day and the upper end of the range is any amountbetween 1 mg/day and 4000 mg/day (e.g., 5 mg/day and 100 mg/day, 150mg/day and 500 mg/day). In other embodiments, a compound herein, isadministered at a dosage of any dosage range in which the low end of therange is any amount between 0.1 mg/kg/day and 90 mg/kg/day and the upperend of the range is any amount between 1 mg/kg/day and—32 1 00 mg/kg/day(e.g., 0.5 mg/kg/day and 2 mg/kg/day, 5 mg/kg/day and 20 mg/kg/day). Thedosing interval can be adjusted according to the needs of theindividual. For longer intervals of administration, extended release ordepot formulations can be used. The dosing can be commensurate withintravenous administration. For instance, the compound can beadministered, such as in a pharmaceutical composition that is amenableto intravenous administration, in an amount of between about 0.01μg/kg/min to about 100 μg/kg/min or between about 0.05 μg/kg/min toabout 95 μg/kg/min or between about 0.1 μg/kg/min to about 90 μg/kg/minor between about 1.0 μg/kg/min to about 80 μg/kg/min or between about10.0 μg/kg/min to about 70 μg/kg/min or between about 20 μg/kg/min toabout 60 μg/kg/min or between about 30 μg/kg/min to about 50 μg/kg/minor between about 0.01 μg/kg/min to about 1.0 μg/kg/min or between about0.01 μg/kg/min to about 10 μg/kg/min or between about 0.1 μg/kg/min toabout 1.0 μg/kg/min or between about 0.1 μg/kg/min to about 10 μg/kg/minor between about 1.0 μg/kg/min to about 5 μg/kg/min or between about 70μg/kg/min to about 100 μg/kg/min or between about 80 μg/kg/min to about90 μg/kg/min. In one variation, the compound is administered to anindividual, such as in a pharmaceutical composition that is amenable tointravenous administration, in an amount of at least about 0.01μg/kg/min or at least about 0.05 μg/kg/min or at least about 0.1μg/kg/min or at least about 0.15 μs/kg/min or at least about 0.25μg/kg/min or at least about 0.5 μg/kg/min or at least about 1.0μg/kg/min or at least about 1.5 μg/kg/min or at least about 5.0μg/kg/min or at least about 10.0 μg/kg/min or at least about 20.0μg/kg/min or at least about 30.0 μg/kg/min or at least about 40.0μg/kg/min or at least about 50.0 μg/kg/min or at least about 60.0μg/kg/min or at least about 70.0 μg/kg/min or at least about 80.0μg/kg/min or at least about 90.0 μg/kg/min or at least about 100.0μg/kg/min or more. In another variation, the compound is administered toan individual, such as in a pharmaceutical composition that is amenableto intravenous administration, in an amount of less than about 100.0μg/kg/min or less than about 90.0 μg/kg/min or less than about 80.0μg/kg/min or less than about 80.0 μg/kg/min or less than about 70.0μg/kg/min or less than about 60.0 μg/kg/min or less than about 50.0μg/kg/min or less than about 40.0 μg/kg/min or less than about 30.0μg/kg/min or less than about 20.0 μg/kg/min or less than about 10.0μg/kg/min or less than about 5.0 μg/kg/min or less than about 2.5μg/kg/min or less than about 1.0 μs/kg/min or less than about 0.5μg/kg/min or less than about 0.05 μg/kg/min or less than about 0.15μg/kg/min or less than about 0.1 μg/kg/min or less than about 0.05μg/kg/min or less than about 0.01 μg/kg/min.

The invention further provides kits comprising one or more compounds asdescribed herein. The kits may employ any of the compounds disclosedherein and instructions for use. The compound may be formulated in anyacceptable form. The kits may be used for any one or more of the usesdescribed herein, and, accordingly, may contain instructions for any oneor more of the stated uses (e.g., treating and/or preventing and/ordelaying the onset and/or the development of heart failure orischemia/reperfusion injury).

Kits generally comprise suitable packaging. The kits may comprise one ormore containers comprising any compound described herein. Each component(if there is more than one component) can be packaged in separatecontainers or some components can be combined in one container wherecross-reactivity and shelf life permit.

The kits may optionally include a set of instructions, generally writteninstructions, although electronic storage media (e.g., magnetic disketteor optical disk) containing instructions are also acceptable, relatingto the use of component(s) of the methods of the present invention(e.g., treating, preventing and/or delaying the onset and/or thedevelopment of heart disease or ischemia/reperfusion injury). Theinstructions included with the kit generally include information as tothe components and their administration to an individual.

The following examples are provided to illustrate various embodiments ofthe invention, and are not intended to limit the invention in anymanner.

Examples

In the following examples, All HPLC analysis was carried out using a CTCPAL HTS autosampler with a waters 2487 uv detector powered by an AgilentG1312A binary pump. The following method and column were used fordetermination of retention time (TR) 0-100% B [MeCN: H₂O: 0.2% HCO₂H],2.5 min gradient, 0.5 min hold, 215 nm, Atlantis dC18 2.1×50 mm, 5 μm.

All NMR were recorded on a Bruker AVANCE 400 MHz spectrometer operatingat ambient probe temperature using an internal deuterium lock. Chemicalshifts are reported in parts per million (ppm) at lower frequencyrelative to tetramethylsilane (TMS). Standard abbreviations are usedthroughout (s singlet; br. s broad singlet; d doublet; dd doublet ofdoublets; t triplet; q quartet; quin quintet; m multiplet). Couplingconstants are reported in Hertz (Hz).

All microwave reactions were carried out using a CEM explorer systemfollowing standard methods.

Example 1. Preparation of Compounds According to General Synthesis ofScheme A

The preparation of 2-bromo-N-hydroxy-benezene-sulfonamide is detailedbelow as a representative example of the synthetic method exemplified inScheme A.

To a solution of hydroxylamine hydrochloride (0.82 g, 0.012 mol) inwater (1.2 ml) at 0° C. was added a solution of potassium carbonate (1.6g, 0.012 mol) in water (1.8 ml) dropwise maintaining an internalreaction temperature between 5° C. and 15° C. The reaction mixture wasstirred for 15 minutes, whereupon THF (6 ml) and MeOH (1.5 ml) wereadded. 2-Bromobenzene sulfonyl Chloride (1.51 g, 0.006 mol) was addedportionwise maintaining a temperature below 15° C. and the reactionmixture was stirred at ambient temperature until complete consumption ofthe sulfonyl chloride was observed by TLC. The resulting suspension wasconcentrated to remove any volatiles and the aqueous suspension wasextracted with diethyl ether (2×100 ml). The organic portion was driedover magnesium sulfate, filtered and concentrated in vacuo to yield thecrude N-hydroxy sulfonamide. Purification was achieved by chromatographyon silica gel eluting with hexane:ether (1:1 v:v) to give the parentcompound as a white solid (0.30 g, 20% yield) δH (400 MHz, DMSO)9.81-9.84 (1H, m), 9.78-9.81 (1H, m), 7.99 (1H, dd, 7.7, 1.8 Hz), 7.86(1H, dd, 7.6, 1.5 Hz), 7.55-7.64 (2H, m); TR=1.44 min.

Using the experimental conditions reported above and the appropriatestarting materials, which were either commercially available orsynthesised using standard methodology, the following compounds wereprepared:

Systematic name 1-H NMR T_(R) 2,6-Dichloro-N-hydroxy δ_(H) (400 MHz,DMSO) 9.92 (1H, d, 3.0 Hz), 1.52 benzene sulfonamide 9.77 (1H, d, 2.9Hz), 7.59-7.69 (3H, m) 4-Bromo-N-hydroxy δ_(H) (400 MHz, DMSO) 9.70-9.72(1H, m), 1.56 benzene sulfonamide 9.67-9.69 (1H, m), 7.83-7.88 (2H, m),7.73-7.78 (2H, m) 3-Bromo-N-hydroxy δ_(H) (400 MHz, DMSO) 9.75 (1H, d,8.1 Hz), 1.57 benzene sulfonamide 9.77 (1H, s), 7.92 (1H, d, 8.1 Hz),7.95 (1H, t, 1.7 Hz), 7.84 (1H, d, 7.8 Hz), 7.60 (1H, t, 7.9 Hz)2-Bromo-4-fluoro-N- δ_(H) (400 MHz, DMSO) 9.86 (1H, d, 2.7 Hz), 1.52hydroxy benzene 9.81 (1H, d, 2.9 Hz), 8.04 (1H, dd, 8.9, sulfonamide 6.0Hz), 7.88 (1H, dd, 8.6, 2.4 Hz), 7.52 (1H, td, 8.6, 2.4 Hz)2,5-Di-trifluoromethyl-N- δ_(H) (400 MHz, DMSO) 10.49 (1H, br. s.), 1.88hydroxy benzene 10.18 (1H, s), 8.42 (1H, s), 8.25-8.33 (2H, m)sulfonamide Thiophene-2-N- _(δH) (400 MHz, DMSO) 9.77 (1H, s), 9.67 (1H,0.99 hydroxysulfonamide s), 8.02 (1H, dd, 4.9, 1.2 Hz), 7.65 (1H, d, 3.7Hz), 7.23 (1H, dd, 4.6, 3.9 Hz) 4-Bromo-thiophene-3-N- δ_(H) (400 MHz,DMSO) 9.84 (1H, d, 3.2 Hz), 1.32 hydroxysulfonamide 9.80-9.82 (1H, m),8.06 (1H, d, 5.1 Hz), 7.30 (1H, d, 5.1 Hz) 2-Chloro-4-fluoro-N- δ_(H)(400 MHz, DMSO) 9.84 (1H, d, 2.9 Hz), 1.46 hydroxy benzene 9.80 (1H, d,2.9 Hz), 8.04 (1H, dd, 8.9, sulfonamide 6.0 Hz), 7.73 (1H, dd, 8.8, 2.7Hz), 7.47 (1H, td, 8.5, 2.6 Hz) 2,3-Dichloro-N-hydroxy δ_(H) (400 MHz,DMSO) 10.01 (1H, d, 2.7 Hz), 1.63 benzene sulfonamide 9.87 (1H, d, 2.7Hz), 7.98 (1H, d, 7.8 Hz), 7.97 (1H, s), 7.60 (1H, t, 8.1 Hz)2-Chloro-4-bromo-N- δ_(H) (400 MHz, DMSO) 9.90 (1H, s), 9.83 (1H, 1.70hydroxy benzene s), 8.01 (1H, d, 2.0 Hz), 7.86-7.91 (1H, m), sulfonamide7.79-7.84 (1H, m) Thiophene-3-N-hydroxy δ_(H) (400 MHz, DMSO) 9.60 (1H,d, 3.2 Hz), 0.90 sulfonamide 9.53 (1H, d, 3.2 Hz), 8.24 (1H, dd, 2.8,1.1 Hz), 7.75 (1H, dd, 5.0, 3.1 Hz), 7.36 (1H, dd, 5.1, 1.2 Hz)2-Nitro-4-trifluoromethyl-N- δ_(H) (400 MHz, DMSO) 10.46 (1H, d, 1.7Hz), 1.80 hydroxy benzene 10.17 (1H, d, 2.3 Hz), 8.60 (1H, s), 8.36 (1H,sulfonamide s), 8.26 (1H, d, 8.2 Hz) 3,4,5-trifluoro-N-hydroxy δ_(H)(400 MHz, DMSO) 9.89 (1H, d, 3.0 Hz), 1.58 benzene sulfonamide 9.88 (1H,d, 3.0 Hz), 7.76 (2H, t, 6.7 Hz) 2-Iodo-N-hydroxy benzene δ_(H) (400MHz, DMSO) 9.78 (1H, d, 2.8 Hz), 1.50 sulfonamide 9.72 (1H, d, 2.9 Hz),8.15 (1H, dd, 7.8, 0.9 Hz), 7.96 (1H, dd, 8.0, 1.5 Hz), 7.61 (1H, dd,15.4, 0.9 Hz), 7.33 (1H, td, 7.6, 1.5 Hz) 4-Phenyl-5-trifluoromethyl-δ_(H) (400 MHz, DMSO) 9.70 (1H, s), 9.58 (1H, 2.00 thiophene-3-N- br.s.), 8.60 (1H, s), 7.37-7.44 (3H, m), hydroxysulfonamide 7.31-7.33 (2H,m) 1,3 Di-N-hydroxy benzene δ_(H) (400 MHz, DMSO) 9.88 (2H, br. s.),9.81 1.03 sulfonamide (2H, s), 8.28 (1H, t, 1.7 Hz), 8.14 (2H, dd, 7.8,1.8 Hz), 7.90 (1H, t, 7.9 Hz) 2,5-Di-fluoro-N-hydroxy δ_(H) (400 MHz,DMSO) 9.91 (2H, s), 7.77 (1H, 1.18 benzene sulfonamide tt, 8.5, 6.1 Hz),7.31 (2H, t, 8.9 Hz) N-Hydroxy-2- δ_(H) (400 MHz, DMSO) 10.12 (1H, d,3.5 Hz), 1.31 methanesulfonyl-benzene 8.96 (1H, d, 3.5 Hz), 8.25-8.27(1H, m), sulfonamide 8.16-8.21 (1H, m), 7.99-8.04 (2H, m), 3.47 (3H, s)2,4-Di-bromo-N-hydroxy δ_(H) (400 MHz, DMSO) 9.93 (1H, d, 2.9 Hz), 1.76benzene sulfonamide 9.84 (1H, d, 2.9 Hz), 8.16 (1H, d, 1.5 Hz), 7.88(1H, s), 7.87 (1H, d, 1.7 Hz) 2-Chloro-4-trifluoromethyl- δ_(H) (400MHz, DMSO) 10.13 (1H, d, 2.9 Hz), 1.81 N-hydroxy benzene 9.94 (1H, d,2.7 Hz), 8.15 (1H, d, 1.0 Hz), sulfonamide 8.19 (1H, d, 8.3 Hz), 7.99(1H, dd, 8.4, 1.1 Hz) 2,4,6-Tri-isopropyl-N- δ_(H) (400 MHz, DMSO) 9.34(1H, d, 3.0 Hz), 2.30 hydroxy benzene 9.28 (1H, d, 2.9 Hz), 7.24 (2H,s), 4.05-4.19 sulfonamide (2H, sept, 6.8 Hz), 2.87-2.97 (1H, sept, 6.9Hz), 1.20 (18H, t, 6.9 Hz) 3,5-Dimethyl-isoxazole-4- δ_(H) (400 MHz,DMSO) 9.80 (1H, d, 3.2 Hz), 1.16 N-hydroxy sulfonamide 9.64 (1H, d, 3.2Hz), 2.60 (3H, s), 2.34 (3H, s) 2,4-Di-fluoro-N-hydroxy δ_(H) (400 MHz,DMSO) 9.81 (1H, d, 2.9 Hz), 1.28 benzene sulfonamide 9.77 (1H, d, 2.9Hz), 7.88 (1H, td, 8.6, 6.4 Hz), 7.56 (1H, ddd, 10.3, 9.4, 2.6 Hz), 7.33(1H, td, 7.7, 1.7 Hz) 4-Bromo-2,5-dichloro- δ_(H) (400 MHz, DMSO) 9.92(1H, d, 2.4 Hz), 1.79 thiophene-3-N-hydroxy 9.86 (1H, d, 2.7 Hz)sulfonamide Quinoline-8-N-hydroxy δ_(H) (400 MHz, DMSO) 9.83 (1H, d, 3.7Hz), 1.34 sulfonamide 9.21 (1H, d, 3.7 Hz), 9.09 (1H, dd, 4.4, 1.7 Hz),8.60 (1H, dd, 8.3, 1.7 Hz), 8.39 (1H, s), 8.39 (1H, dd, 16.4, 1.2 Hz),7.83 (1H, d, 7.8 Hz), 7.76 (1H, dd, 8.4, 4.3 Hz) 5-Methyl- δ_(H) (400MHz, DMSO) 9.90 (1H, d, 3.2 Hz), 1.81 benzo[b]thiophene-2-N- 9.86 (1H,d, 3.1 Hz), 7.97-8.01 (2H, m), 7.87 hydroxy sulfonamide (1H, s), 7.39(1H, dd, 8.6, 1.5 Hz), 2.44 (3H, s) Benzofuran-2-N-hydroxy δ_(H) (400MHz, DMSO) 10.25 (1H, d, 2.8 Hz), 1.58 sulfonamide 9.87 (1H, d, 2.8 Hz),7.84 (1H, d, 7.8 Hz), 7.72 (1H, d, 0.8 Hz), 7.75 (1H, d, 8.5 Hz), 7.56(1H, ddd, 8.4, 7.2, 1.3 Hz), 7.42 (1H, dd, 15.1, 0.6 Hz)1-Methyl-1H-pyrazole-3-N- δ_(H) (400 MHz, DMSO) 9.61 (1H, d, 3.2 Hz),0.47 hydroxy sulfonamide 9.49 (1H, d, 1.0 Hz), 7.89 (1H, d, 2.2 Hz),6.68 (1H, d, 2.2 Hz), 3.94 (3H, s) 4-Fluoro-naphthalene-1-N- δ_(H) (400MHz, DMSO) 9.87 (1H, d, 2.9 Hz), 1.72 hydroxy sulfonamide 9.64 (1H, d,2.9 Hz), 8.75 (1H, d, 8.3 Hz), 8.19-8.25 (2H, m), 7.81 (2H, ddd, 12.0,8.3, 1.2 Hz), 7.56 (1H, dd, 10.0, 8.3 Hz) 3-Bromo-thiophene-2-N- δ_(H)(400 MHz, DMSO) 9.83-9.86 (1H, m), 1.32 hydroxy sulfonamide 9.81-9.83(1H, m), 8.05 (1H, d, 5.1 Hz), 7.30 (1H, d, 5.1 Hz) Propane-2-N-hydroxyδ_(H) (400 MHz, DMSO) 9.44 (1H, d, 2.2 Hz), sulfonamide 9.24 (1H, s),3.39-3.50 (1H, sept, 6.9 Hz), 1.25 (6H, d, 6.9 Hz) Methyl-N-hydroxyδ_(H) (400 MHz, DMSO) 9.56 (1H, d, 3.4 Hz), sulfonamide 9.03 (1H, d, 3.4Hz), 2.92 (3H, s) Biphenyl-2-N-hydroxy δ_(H) (400 MHz, DMSO) 9.63 (1H,br. s.), 9.51 1.74 sulfonamide (1H, s), 8.00 (1H, dd, 7.8, 1.2 Hz), 7.67(1H, dd, 7.5, 1.3 Hz), 7.62 (1H, dd, 7.7, 1.3 Hz), 7.34-7.41 (6H, m)

The following procedure, which may involve modifications to therepresentative reaction above, was used in the preparation of thefollowing compounds (1-10):

2-Fluoro-N-hydroxybenzenesulfonamide (1). ¹H NMR (400 MHz, DMSO-d₆) δ9.78 (d, 1H), 9.73 (d, 1H), 7.81 (dt, 1H), 7.76 (m, 1H), 7.44 (m, 2H);mp 127-129° C.

2-Chloro-N-hydroxybenzenesulfonamide (2). ¹H NMR (400 MHz, DMSO-d₆) δ9.80 (s, 1H), 9.78 (bs, 1H), 8.00 (d, 1H), 7.68 (d, 2H), 7.56 (m, 1H);mp 152-155° C. with decomposition

2-Bromo-N-hydroxybenzenesulfonamide (3). ¹H NMR (400 MHz, DMSO-d₆) δ9.82 (s, 1H), 9.78 (s, 1H), 8.00 (dd, 1H), 7.86 (dd, 1H), 7.60 (m, 2H);mp 156-159° C. with decomposition

2-(Trifluoromethyl)-N-hydroxybenzenesulfonamide (4). ¹H NMR (400 MHz,DMSO-d₆) δ 10.12 (d, 1H), 9.91 (d, 1H), 8.12 (d, 1H), 8.01 (d, 1H), 7.93(t, 1H), 7.87 (t, 1H); mp 124-127° C. with decomposition.

5-Chlorathiophene-2-sulfohydroxainic acid (5). ¹H NMR (400 MHz, DMSO-d₆)δ 9.90 (bps, 1H), 9.72 (s, IH), 7.54 (d, 1H), 7.30 (d, 1H); ¹³C NMR (100MHz, DMSO-d₆) δ 136.0, 135.5, 133.4, 127.9; mp 94-95° C. withdecomposition.

2,5-Dichlorothiophene-3-sulfohydroxamic acid (6). ¹H NMR (400 MHz,DMSO-d₆) δ 9.88 (s, 2H), 7.30 (s, IH); ¹³C NMR (100 MHz, DMSO-d₆) δ133.3, 131.7, 127.1, 126.0; mp 118-122° C. with decomposition.

4-Fluoro-N-hydroxybenzenesulfonamide (7). NMR Previously reported.

4-(Trifluoromethyl)-N-hydroxybenzenesulfonamide (8). ¹H NMR (400 MHZ,DMSO-d₆) δ 9.85 (d, 1H), 9.80 (d, 1H), 8.05 (m, 4H); mp 117-121° C. withdecomposition.

4-Cyano-N-hydroxybenzenesulfonamide (9). ¹H NMR (400 MHZ, DMSO-d₆) δ9.88 (d, 1H), 9.81 (d, 1H), 8.12 (d, 2H), 8.00 (d, 2H); mp 151-155° C.with decomposition.

4-Nitro-N-hydroxybenzenesulfonamide (10). NMR Previously reported.

60 mmol (2 eq.) of hydroxylamine hydrochloride was dissolved in 12 mL ofwater and cooled to 0° C. in an ice bath. A solution of 60 mmol (2 eq.)of potassium carbonate in 18 mL of water was added dropwise withstirring. The solution was stirred for 15 min, at which time wassequentially added 25 mL of methanol and 75 mL of tetrahydrofuran. Asolution of 30 mmol (1 eq.) of sulfonyl chloride in 10 mL oftetrahydrofuran was added dropwise, and the resultant solution wasallowed to warm to room temperature with stirring for 2-3 hours. Thevolatiles were evaporated under reduced pressure and 100 mL water wasadded. The aqueous solution was acidified to approximately pH 3 with 1 Naqueous hydrochloric acid, and extracted with diethyl ether (2×100 mL).The organic layer was dried over magnesium sulfate and evaporated toyield in all cases crystalline solids with sufficient purity (25-50%yield).

Example 2. Preparation of Compounds According to General Synthesis ofScheme B

The preparation of N-benzyloxy-2-bromo-benzenesulfonamide

is detailed below as a representative example of the synthetic methodexemplified in Scheme B.

To a suspension of O-benzylhydroxylamine hydrochloride (3.75 g, 23.48mmol) in MeOH (3 ml) and water (3.6 ml) was added a solution ofpotassium carbonate (3.24 g, 23.48 mmol) in water (3.6 ml), maintainingan internal reaction temperature below 10° C. The reaction mixture wasstirred for 5 minutes, whereupon THF (12 ml) and 2-bromobenzene sulfonylchloride (3 g, 11.74 mmol) were added. The reaction mixture was stirredat ambient temperature until complete consumption of the sulfonylchloride was observed by TLC. The resulting suspension was concentratedin vacuo to remove any volatiles, and the aqueous suspension wasextracted with diethyl ether (3×100 ml). The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo to yield thecrude target compound. Purification was achieved by trituration of thesolid in heptane, followed by filtration and further washing of thesolid with heptane, to give the expected compound as a white solid (3.62g, 90% yield). 0.54400 MHz, DMSO) 10.83 (1H, s), 8.04 (1H, d, 1.7 Hz),8.02 (1H, d, 1.9 Hz), 7.57-7.66 (2H, m), 7.30-7.36 (5H, m), 4.87 (1H,s); T_(R)=2.15.

N-benzyloxy-2-bromo-benzenesulfonamide may be further derivitized asdetailed in the synthesis of N-benzyloxy-2-phenyl-benzenesulfonamide

A microwave vial was charged successively withN-benzyloxy-2-bromo-benzenesulfonamide (0.2 g, 0.58 mmol), benzeneboronic acid (0.11 g, 0.88 mmol), Pd(dppf)Cl₂ (0.05 g, 0.06 mmol), THF(3 ml), then a solution of potassium carbonate in water (2N, 1.5 ml).The mixture was heated in the microwave at 130° C. for 15 minutes (5minutes ramp time, power=150 W). The reaction mixture was then dilutedwith ethyl acetate (20 ml), and the organic layer was washed with water(2×20 ml). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The crude mixture was then purified by columnchromatography on silica gel, eluting with heptane:ethyl acetate (9:1v:v) to give the target compound as a colourless oil (0.12 g, 60%yield). 84400 MHz, DMSO) 10.61 (1H, s), 8.06 (1H, dd, 7.8, 1.2 Hz), 7.77(1H, td, 7.3, 1.5 Hz), 7.69 (1H, td, 7.5, 1.4 Hz), 7.40-7.46 (9H, m),7.33-7.35 (2H, m), 4.82 (2H, s). T_(R)=1.74 min.

N-benzyloxy-2-phenyl-benzenesulfonamide may be deprotected to thecorresponding N-hydroxysulfonamide as detailed below:

To a suspension of N-benzyloxy-2-phenyl-benzenesulfonamide (1.39 g, 4.1mmol) in EtOH (20 ml) was added 10% palladium on charcoal (0.14 g). Thereaction mixture was stirred under a hydrogen atmosphere at ambienttemperature and atmospheric pressure overnight. The reaction mixture wasfiltered through microfibre glass paper. The resulting filtrate wasconcentrated in vacuo, and the residue purified by column chromatographyon silica gel eluting with heptane:ethyl acetate (gradient from 9:1 to8:2 v:v) to give the target compound as a white solid (0.24 g, 22%yield). δ_(H)(400 MHz, DMSO) 9.68 (1H, s), 9.57 (1H, s), 8.06 (1H, dd,7.8, 1.2 Hz), 7.74 (1H, td, 7.3, 1.5 Hz), 7.67 (1H, td, 7.6, 1.3 Hz),7.40-7.46 (6H, m).

Example 3. Preparation of Compounds According to General Synthesis ofScheme C

The preparation of4-Bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide

is detailed below as a representative example of the synthetic methodexemplified in Scheme C.

To a solution of O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (1.83 g,15.65 mmol) in water (1.6 ml) at 0° C. was added a solution of potassiumcarbonate (1.1 g, 7.83 mmol) in water (2.4 ml) dropwise maintaining aninternal reaction temperature below 10° C. After 15 minutes MeOH (2 ml)and THF (8 ml) were added was dropwise, followed by 4-bromobenzenesulfonyl chloride (2 g, 7.83 mmol) portionwise. The reaction mixture wasstirred at ambient temperature until complete consumption of thesulfonyl chloride was observed by TLC. The resulting suspension wasconcentrated to remove any volatiles and the aqueous suspension wasextracted with diethyl ether (3×100 ml). The organic portion was driedover sodium sulfate, filtered and concentrated in vacuo to yield thecrude target compound. Purification was achieved by columnchromatography on silica gel eluting with a heptane:ethyl acetate(gradient from 9:1 to 7:3 v:v) to give the target compound as a whitesolid (2.1 g, 80% yield). δ_(H)(400 MHz, DMSO) 10.53 (1H, s), 7.86-7.90(2H, m), 7.75-7.79 (2H, m), 4.94 (1H, t, 2.93 Hz), 3.70-3.76 (1H, m),3.48-3.52 (1H, m). 1.59-1.68 (111, m), 1.39-1.52 (5H, m); T_(R)=2.03min.

4-Bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide may be furthermodified to biphenyl-2-N-hydroxysulfonamide as detailed below:

To a solution of 4-bromo-N-(tetrahydro-pyran-2-yloxy)-benzenesulfonamide(0.1 g, 0.3 mmol) in MeOH (2 ml), was added MP-tosic acid resin (91 mg,loading 3.3 mmol/g). The mixture was stirred at ambient temperatureuntil complete consumption of the starting material was observed by LC.The resin was then filtered off, and washed with MeOH (2×5 ml). Theresulting filtrate was concentrated in vacuo to afford the targetcompound as colourless oil (0.08 g, 100% yield). δ_(H)(400 MHz, DMSO)9.70 (1H, d, 3.2 Hz), 9.67 (1H, d, 3.4 Hz), 7.84-7.88 (2H, m), 7.73-7.77(2H, m); T_(R)=1.60 min

Example 4. Kinetics of HNO Release

The decomposition rates of the compounds may be determined by UV-Visspectroscopy.

The decomposition of compounds 1-4 and 6 from Example 1 was monitored byUV-Vis spectroscopy in 0.1 M PBS buffer at pH 7.4 and 37° C. Thespectral behavior was isosbectic and the time course fit well to asingle exponential. The decomposition rate is increased in aeratedsolutions compared to argon-saturated solutions because of theintroduction of an oxygen-dependent decomposition pathway that, for theparent N-hydroxybenzenesulfonamide (PA) has been shown to release NO(Bonner, F. T.; Ko., Y. Inorg. Chem. 1992, 31, 2514-2519). Decompositionkinetics for compounds 5, 7-10 of Example 1 are not first-order and thusonly approximate half-lives are reported. Compounds with more than onenumber in a single column in the table below indicates the results oftwo experiments for the same compound.

Compound t_(1/2) (Ar) (min) t_(1/2) (air) (min) k_(O2)/k_(Ar) 1 17.5;18.0 2.67; 4.0 5.82 2 3.61; 4.0  1.75; 1.9 1.06 3 1.05; 2.1  0.68; 1.20.55 4 0.96; 1.2  0.55; 0.6 0.75 5 18.8 6.3 6  9.17  2.60 2.52 7 72.1;72.2  10.0; 10.0 8 33.0; 33.0  7.0; 7.0 9 17.8 4.0 10 5.78; 19.2  3.3;4.2

Example 5. HNO Production Via N₂O Quantification

HNO production of the compounds may be determined by UV-Visspectroscopy.

Nitrous oxide is produced via the dimerization and dehydration of HNO,and is the most common marker for HNO production (Fukuto, J. M.;Bartberger, M. D.; Dutton, A. S.; Paolocci, N.; Wink, D. A.; Houk, K. N.Chem. Res. Toxicol. 2005, 18, 790-801). HNO, however, can also bepartially quenched by oxygen to yield a product that does not produceN₂O (See, (a) Mincione, F.; Menabuoni, L.; Briganti, F.; Mincione, G.;Scozzafava, A.; Supuran, C. T. J. Enzyme Inhibition 1998, 13, 267-284and (b) Scozzafava, A.; Supuran, C. T. J. Med. Chem. 2000, 43,3677-3687.) Using Angeli's salt (AS) as a benchmark, the relativeamounts of N₂O released from compounds 2-4 from Example 1 was examinedvia GC headspace analysis. The results, shown in FIG. 1, show that theamounts of N₂O released from compounds 2-4 are comparable to the amountreleased from AS under both argon and air.

The ability of compounds to donate nitroxyl at pH 7.4 in PBS buffer at37° C. was assessed. In particular, the compounds of Tables 1-3 andcertain compounds from Table 4 were tested and their nitroxyl donatingability at pH 7.4 in PBS buffer at 37° C. was assessed. The compoundstested, with the exception of 2-phenyl-N-hydroxylbenzenesulfonamide, allproduced detectable levels of N₂O, indicating their ability to donatenitroxyl. 2-phenyl-N-hydroxylbenzenesulfonainide may be retested toconfirm whether it is a nitroxyl donor.

Example 6. Use of an In Vitro Model to Determine the Ability ofCompounds of the Invention to Treat, Prevent and/or Delay the Onsetand/or the Development of a Disease or Condition Responsive to NitroxylTherapy

a. Cardiovascular Diseases or Conditions.

In vitro models of cardiovascular disease can also be used to determinethe ability of any of the compounds described herein to treat, preventand/or delay the onset and/or the development of a cardiovasculardisease or condition in an individual. An exemplary in vitro model ofheart disease is described below.

In-vitro models could be utilized to look at vasorelaxation propertiesof the compounds. Isometric tension in isolated rat thoracic aortic ringsegment can be measured as described previously by Crawford, J. H.,Huang, J, Isbell, T. S., Shiva, S., Chacko, B. K., Schechter, A.,Darley-Usmar, V. M., Kerby, J. D., Lang, J. D., Krauss, D., Ho, C.,Gladwin, M. T., Patel, R. P., Blood 2006, 107, 566-575. Upon sacrificeaortic ring segments are excised and cleansed of fat and adheringtissue. Vessels are then cut into individual ring segments (2-3 mm inwidth) and suspended from a force-displacement transducer in a tissuebath. Ring segments are bathed at 37° C. in a bicarbonate-buffered,Krebs-Henseleit (K-H) solution of the following composition (mM): NaCl118; KCl 4.6; NaHCO₃ 27.2; KH₂PO₄ 1.2; MgSO₄ 1.2; CaCl₂ 1.75; Na₂EDTA0.03; and glucose 11.1 and perfused continuously with 21% O₂/5% CO₂/74%N₂. A passive load of 2 g is applied to all ring segments and maintainedat this level throughout the experiments. At the beginning of eachexperiment, indomethacin-treated ring segments are depolarized with KCl(70 mM) to determine the maximal contractile capacity of the vessel.Rings are then washed extensively and allowed to equilibrate. Forsubsequent experiments, vessels are submaximally contracted (50% of KClresponse) with phenylephrine (PE, 3×10⁻⁸-10⁻⁷ M), and L-NMMA, 0.1 mM, isalso added to inhibit eNOS and endogenous NO production. After tensiondevelopment reaches a plateau, nitroxyl donating compounds are addedcumulatively to the vessel bath and effects on tension monitored.

In vitro models can be utilized to determine the effects of nitroxyldonating compounds in changes in developed force and intracellularcalcium in heart muscles. Developed force and intracellular calcium canbe measured in rat trabeculae from normal or diseased (i.e. rats withcongestive heart failure or hypertrophy) as described previously (Gao WD, Atar D, Backx P H, Marbán E. Circ Res. 1995; 76:1036-1048). Rats(Sprague-Dawley, 250-300 g) are used in these experiments. The rats areanesthetized with pentobarbital (100 mg/kg) via intra-abdominalinjection, the heart exposed by mid-sternotomy, rapidly excised andplaced in a dissection dish. The aorta is cannulated and the heartperfused retrograde (˜15 mM/min) with dissecting Krebs-Henseleit (H-K)solution equilibrated with 95% O₂ and 5% CO₂. The dissecting K-Hsolution is composed of (mM): NaCl 120, NaHCO₃ 20, KCl 5, MgCl 1.2,glucose 10, CaCl₂ 0.5, and 2,3-butanedione monoximine (BDM) 20, pH7.35-7.45 at room temperature (21-22° C.). Trabeculae from the rightventricle of the heart are dissected and mounted between a forcetransducer and a motor arm and superfused with normal K-H solution (KCl,5 mM) at a rate of ˜10 ml/min and stimulated at 0.5 Hz. Dimensions ofthe muscles are measured with a calibration reticule in the ocular ofthe dissection microscope (×40, resolution ˜10 μm).

Force is measured using a force transducer system and is expressed inmilli newtons per square millimeter of cross-sectional area. Sarcomerelength is measured by laser diffraction. Resting sarcomere length is setat 2.20-2.30 μm throughout the experiments.

Intracellular calcium is measured using the free acid form of fura-2 asdescribed in previous studies (Gao et al., 1994; Backx et al., 1995; Gaoet al., 1998). Fura-2 potassium salt is microinjected iontophoreticallyinto one cell and allowed to spread throughout the whole muscle (via gapjunctions). The tip of the electrode (˜0.2 μm in diameter) is filledwith fura-2 salt (1 mM) and the remainder of the electrode was filledwith 150 mM KCl. After a successful impalement into a superficial cellin non-stimulated muscle, a hyperpolarizing current of 5-10 nA is passedcontinuously for ˜15 min. Fura-2 epifluorescence is measured by excitingat 380 and 340 nm. Fluorescent light is collected at 510 nm by aphotomultiplier tube. The output of photomultiplier is collected anddigitized. Ryanodine (1.0 μM) is used to enable steady-state activation.After 15 min of exposure to ryanodine, different levels of tetanizationsare induced briefly (˜4-8 seconds) by stimulating the muscles at 10 Hzat varied extracellular calcium (0.5-20 mM). All experiments areperformed at room temperature (20-22° C.).

b. Diseases or Conditions Implicating Ischemia/Reperfusion.

In vitro models can also be used to determine the ability of any of thecompounds described herein to treat, prevent and/or delay the onsetand/or the development of a disease or condition implicatingischemia/reperfusion injury in an individual.

Example 7. Use of In Vivo and/or Ex Vivo Models to Determine the Abilityof Compounds of the Invention to Treat, Prevent and/or Delay the Onsetand/or the Development of a Disease or Condition Responsive to NitroxylTherapy

a. Cardiovascular Diseases or Conditions.

In vivo models of cardiovascular disease can also be used to determinethe ability of any of the compounds described herein to treat, preventand/or delay the onset and/or the development of a cardiovasculardisease or condition in an individual. An exemplary animal model ofheart disease is described below.

In vivo cardiovascular effects obtained with a nitroxyl donor compoundmay be assessed in a control (normal) dog. The study is conducted inadult (25 kg) mongrel (male) dogs chronically instrumented for conscioushemodynamic analysis and blood sampling, as previously described(Katori, T.; Hoover, D. B.; Ardell, J. L.; Helm, R. H.; Belardi, D. F.;Tocchetti, C. G.; Forfia, P. R.; Kass, D. A.; Paolocci, N. Circ. Res.96(2): 2004). Micromanometer transducers in the left ventricle providepressure, while right atrial and descending aortic catheters providefluid-pressures and sampling conduits. Endocardial sonomicrometers(anteriorposterior, septal-lateral) measure short-axis dimensions, apneumatic occluder around the inferior vena cave facilitated pre-loadmanipulations for pressure-relation analysis. Epicardial pacing leadsare placed on the right atrium, and another pair is placed on the rightventricle free wall linked to a permanent pacemaker to induce rapidpacing-cardiac failure. After 10 days of recovery, animals are evaluatedat baseline sinus rhythm and with atrial pacing (120-160 bpm).Measurements include conscious hemodynamic recordings for cardiacmechanics.

Compounds of the invention are administrated to a healthy control dog atthe dose of 1-5 μg/kg/min and the resulting cardiovascular data isobtained.

Demonstration that a compound of the invention improves cardiachemodynamics in hearts with congestive failure: After completingprotocols under baseline conditions, congestive heart failure is inducedby tachypacing (210 bpm×3 weeks, 240 bpm×I week), as previouslydescribed (Katori, T.; Hoover, D. B.; Ardell, J. L.; Helm, R. H.;Belardi, —37 D. F.; Tocchetti, C. G.; Forfia, P. R.; Kass, D. A.;Paolocci, N. Circ. Res. 96(2): 2004). Briefly, end-diastolic pressureand +dP/dt,max are measured weekly to monitor failure progression. Whenanimals demonstrate a rise in EDP more than 2×, and dp/dt,max of >50%baseline, they are deemed ready for congestive heart failure studies.

The values for test compounds are obtained after 15 min continuous i.v.infusion (2.5 or 1.25 μg/kg/min) in control and heart failurepreparations, respectively, both in the absence and in the presence ofvolume restoration. For comparison, the same hemodynamic measurementsare obtained with AS in heart failure preparations.

b. Diseases or Conditions Implicating Ischemia/Reperfusion.

Ex-vivo models of ischemia/reperfusion can also be used to determine theability of any of the compounds described herein to treat, preventand/or delay the onset and/or the development of a disease or conditionimplicating ischemia/reperfusion injury in an individual. An exemplaryex vivo model of ischemia/reperfusion injury is described below.

Male Wistar rats are housed in identical cages and allowed access to tapwater and a standard rodent diet ad libitum. Each animal is anesthetizedwith 1 g/kg urethane i.p. 10 min after heparin (2,500 U, i.m.)treatment. The chest is opened, and the heart is rapidly excised, placedin ice-cold buffer solution and weighed. Isolated rat hearts areattached to a perfusion apparatus and retrogradely perfused withoxygenated buffer solution at 37° C. The hearts are instrumented aspreviously described in Rastaldo et al., “P-450 metabolite ofarachidonic acid mediates bradykinin-induced negative inotropic effect,”Am. J. Physiol., 280:H2823-H2832 (2001), and Paolocci et al.“cGMP-independent inotropic effects of nitric oxide and peroxynitritedonors: potential role for nitrosylation,” Am. J Physiol., 279:H1982-H1988 (2000). The flow is maintained constant (approximately 9mL/min/g wet weight) to reach a typical coronary perfusion pressure of85-90 mm Hg. A constant proportion of 10% of the flow rate is applied bymeans of one of two perfusion pumps (Terumo, Tokyo, Japan) using a 50 mLsyringe connected to the aortic cannula. Drug applications are performedby switching from the syringe containing buffer alone to the syringe ofthe other pump containing the drug (nitroxyl donating compound)dissolved in a vehicle at a concentration 10× to the desired finalconcentration in the heart. A small hole in the left ventricular wallallows drainage of the thebesian flow, and a polyvinyl-chloride balloonis placed into the left ventricle and connected to an electromanometerfor recording of left ventricular pressure (LVP). The hearts areelectrically paced at 280-300 bpm and kept in a temperature-controlledchamber (37° C.). Coronary perfusion pressure (CPP) and coronary floware monitored with a second electromanometer and an electromagneticflow-probe, respectively, both placed along the perfusion line. Leftventricular pressure, coronary flow and coronary perfusion pressure arerecorded using a TEAC R-71 recorder, digitized at 1000 Hz and analyzedoff-line with DataQ-Instruments/CODAS software, which allowquantification of the maximum rate of increase of LVP during systole(dP/dt_(max)).

Hearts are perfused with Krebs-Henseleit solution gassed with 95% O₂ and5% CO₂ of the following composition: 17.7 mM sodium bicarbonate, 127 mMNaCl, 5.1 mM KCl, 1.5 mM CaCl₂, 1.26 mM MgCl₂, 11 mM D-glucose,supplemented with 5 μg/mL lidocaine.

Experimental Compounds. The nitroxyl donors are diluted in bufferimmediately prior to use.

Experimental Protocols. Hearts are allowed to stabilize for 30 min, andbaseline parameters are recorded. Typically, coronary flow is adjustedwithin the first 10 min and kept constant from thereon. After 30 minstabilization, hearts are randomly assigned to one of the treatmentgroups, and subjected to 30 min global, no-flow ischemia, followed by 30min of reperfusion (I/R). Pacing of the hearts is stopped at thebeginning of the ischemic period and restarted after the third minute ofreperfusion.

Hearts in a control group are perfused with buffer for an additional 29min after stabilization. Treated hearts are exposed to a nitroxyl donor(e.g., 1 μM final concentration for about 20 min followed by a 10 minbuffer wash-out period).

In all hearts pacing is suspended at the onset of ischemia and restarted3 minutes following reperfusion. As isolated heart preparations maydeteriorate over time (typically after 2-2.5 hrs perfusion), the re-flowduration is limited to 30 min in order to minimize the effects producedby crystalloid perfusion on heart performance, and consistently withother reports.

Assessment of ventricular function. To obtain the maximal developed LVP,the volume of the intra-ventricular balloon is adjusted to anend-diastolic LVP of 10 mm Hg during the stabilization period, asreported in Paolocci, supra, and Hare et al., “Pertussis toxin-sensitiveG proteins influence nitric oxide synthase III activity and proteinlevels in rat hearts,” J. Clin. Invest., 101:1424-31 (1998). Changes indeveloped LVP, dP/dt_(max) and the end-diastolic value induced by theI/R protocol are continuously monitored. The difference between theend-diastolic LVP (EDLVP) before the end of the ischemic period andduring pre-ischemic conditions is used as an index of the extent ofcontracture development. Maximal recovery of developed LVP anddP/dt_(max) during reperfusion is compared with respective pre-ischemicvalues.

Assessment of myocardial injury. Enzyme release is a measure of severemyocardial injury that has yet to progress to irreversible cell injury.Samples of coronary effluent (2 mL) are withdrawn with a catheterinserted into the right ventricle via the pulmonary artery. Samples aretaken immediately before ischemia and at 3, 6, 10, 20 and 30 min ofreperfusion. LDH release is measured as previously described byBergmeyer & Bernt, “Methods of Enzymatic Analysis,” Verlag Chemie(1974). Data are expressed as cumulative values for the entire reflowperiod.

To corroborate the data relative to myocardial injury, determined by LDHrelease, infarct areas are also assessed in a blinded fashion. At theend of the course (30 min reperfusion), each heart is rapidly removedfrom the perfusion apparatus, and the LV dissected into 2-3 mmcircumferential slices. Following 15 min of incubation at 37° C. in 0.1%solution of nitro blue tetrazolium in phosphate buffer as described inMa et al., “Opposite effects of nitric oxide and nitroxyl onpostischemic myocardial injury,” Proc. Natl. Acad. Sci., 96:14617-14622(1999), unstained necrotic tissue is separated from the stained viabletissue. The areas of viable and necrotic tissue are carefully separateby and independent observer who is not aware of the origin of thehearts. The weight of the necrotic and non-necrotic tissues is thendetermined and the necrotic mass expressed as a percentage of total leftventricular mass.

Data may be subjected to statistical methods such as ANOVA followed bythe Bonferroni correction for post hoc t tests.

Example 8. Use of Human Clinical Trials to Determine the Ability toCombination Therapies of the Invention to Treat, Prevent and/or Delaythe Onset and/or the Development of a Disease or Condition Responsive toNitroxyl Therapy

If desired, any of the compounds described herein can also be tested inhumans to determine the ability of the compound to treat, prevent and/ordelay the onset and/or the development of a disease or conditionresponsive to nitroxyl therapy. Standard methods can be used for theseclinical trials. In one exemplary method, subjects with such a diseaseor condition, such as congestive heart failure, are enrolled in atolerability, pharmacokinetics and pharmacodynamics phase I study of atherapy using the compounds of the invention in standard protocols. Thena phase II, double-blind randomized controlled trial is performed todetermine the efficacy of the compounds using standard protocols.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

All references, publications, patents, and patent applications disclosedherein are hereby incorporated by reference in their entirety.

What is claimed:
 1. A method for modulating in vivo nitroxyl levels,treating a cardiovascular disease or condition, or treating heartfailure, comprising administering to an individual in need thereof (a)an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H; R² isH; R³ is halo, methylsulfonyl or perfluoromethyl; R⁴, R¹, R⁶ and R⁷ areH; and halo is F, Cl, Br or I; and (b) an effective amount of at leastone other positive inotropic agent.
 2. The method of claim 1, whereinthe other positive inotropic agent is selected from a beta-adrenergicreceptor agonist, an inhibitor of phosphodiesterase activity, acalcium-sensitizer, and any combination thereof and the heart failure isacute decompensated heart failure.
 3. The method of claim 1, wherein R³is Cl, Br or I.
 4. The method of claim 3, wherein the other positiveinotropic agent is selected from a beta-adrenergic receptor agonist, aninhibitor of phosphodiesterase activity, a calcium-sensitizer, and anycombination thereof and the heart failure is acute decompensated heartfailure.
 5. The method of claim 1, wherein R³ is methylsulfonyl.
 6. Themethod of claim 5, wherein the other positive inotropic agent isselected from a beta-adrenergic receptor agonist, an inhibitor ofphosphodiesterase activity, a calcium-sensitizer, and any combinationthereof and the heart failure is acute decompensated heart failure. 7.The method of claim 1, wherein R³ is perfluoromethyl.
 8. The method ofclaim 7, wherein the other positive inotropic agent is selected from abeta-adrenergic receptor agonist, an inhibitor of phosphodiesteraseactivity, a calcium-sensitizer, and any combination thereof and theheart failure is acute decompensated heart failure.
 9. A method fortreating, preventing, delaying the onset of, or delaying the developmentof heart failure, comprising administering to an individual in needthereof (a) an effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H; R² isH; R³ is halo, methylsulfonyl or perfluoromethyl; R⁴, R⁵, R⁶ and R⁷ areH; and halo is F, Cl, Br or I; and (b) an effective amount of at leastone other positive inotropic agent.
 10. The method of claim 9, whereinthe other positive inotropic agent is selected from a beta-adrenergicreceptor agonist, an inhibitor of phosphodiesterase activity, acalcium-sensitizer, and any combination thereof and the heart failure isacute decompensated heart failure.
 11. The method of claim 9, wherein R³is Cl, Br or I.
 12. The method of claim 11, wherein the other positiveinotropic agent is selected from a beta-adrenergic receptor agonist, aninhibitor of phosphodiesterase activity, a calcium-sensitizer, and anycombination thereof and the heart failure is acute decompensated heartfailure.
 13. The method of claim 9, wherein R³ is methylsulfonyl. 14.The method of claim 13, wherein the other positive inotropic agent isselected from a beta-adrenergic receptor agonist, an inhibitor ofphosphodiesterase activity, a calcium-sensitizer, and any combinationthereof and the heart failure is acute decompensated heart failure. 15.The method of claim 9, wherein R³ is perfluoromethyl.
 16. The method ofclaim 15, wherein the other positive inotropic agent is selected from abeta-adrenergic receptor agonist, an inhibitor of phosphodiesteraseactivity, a calcium-sensitizer, and any combination thereof and theheart failure is acute decompensated heart failure.
 17. The method ofclaim 1, wherein the other positive inotropic agent is selected fromdopamine, dopexamine, dobutamine, terbutaline, isoproterenol, and anycombination thereof.
 18. The method of claim 9, wherein the otherpositive inotropic agent is selected from dopamine, dopexamine,dobutamine, terbutaline, isoproterenol, and any combination thereof.